<?xml version="1.0"?>
<ownershipDocument>

    <schemaVersion>X0305</schemaVersion>

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    <periodOfReport>2012-04-02</periodOfReport>

    <notSubjectToSection16>0</notSubjectToSection16>

    <issuer>
        <issuerCik>0001532063</issuerCik>
        <issuerName>Express Scripts Holding Co.</issuerName>
        <issuerTradingSymbol>ESRX</issuerTradingSymbol>
    </issuer>

    <reportingOwner>
        <reportingOwnerId>
            <rptOwnerCik>0001299172</rptOwnerCik>
            <rptOwnerName>Hall Jeffrey</rptOwnerName>
        </reportingOwnerId>
        <reportingOwnerAddress>
            <rptOwnerStreet1>C/O EXPRESS SCRIPTS HOLDING COMPANY</rptOwnerStreet1>
            <rptOwnerStreet2>ONE EXPRESS WAY</rptOwnerStreet2>
            <rptOwnerCity>ST. LOUIS</rptOwnerCity>
            <rptOwnerState>MO</rptOwnerState>
            <rptOwnerZipCode>63121</rptOwnerZipCode>
            <rptOwnerStateDescription></rptOwnerStateDescription>
        </reportingOwnerAddress>
        <reportingOwnerRelationship>
            <isDirector>0</isDirector>
            <isOfficer>1</isOfficer>
            <isTenPercentOwner>0</isTenPercentOwner>
            <isOther>0</isOther>
            <officerTitle>EVP &amp; Chief Financial Officer</officerTitle>
            <otherText></otherText>
        </reportingOwnerRelationship>
    </reportingOwner>

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                <value>Common Stock</value>
            </securityTitle>
            <transactionDate>
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            </transactionDate>
            <deemedExecutionDate></deemedExecutionDate>
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                </directOrIndirectOwnership>
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    </nonDerivativeTable>

    <derivativeTable>
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            </conversionOrExercisePrice>
            <transactionDate>
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            <deemedExecutionDate></deemedExecutionDate>
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            <expirationDate>
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        <derivativeTransaction>
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            </conversionOrExercisePrice>
            <transactionDate>
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            </transactionDate>
            <deemedExecutionDate></deemedExecutionDate>
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                <transactionCode>A</transactionCode>
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                </transactionShares>
                <transactionPricePerShare>
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                <transactionAcquiredDisposedCode>
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            <exerciseDate>
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            <expirationDate>
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            </expirationDate>
            <underlyingSecurity>
                <underlyingSecurityTitle>
                    <value>Express Scripts Holding Company Common Stock</value>
                </underlyingSecurityTitle>
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                </underlyingSecurityShares>
            </underlyingSecurity>
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                </sharesOwnedFollowingTransaction>
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            <ownershipNature>
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        <derivativeTransaction>
            <securityTitle>
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            </securityTitle>
            <conversionOrExercisePrice>
                <value>49.495</value>
            </conversionOrExercisePrice>
            <transactionDate>
                <value>2012-04-02</value>
            </transactionDate>
            <deemedExecutionDate></deemedExecutionDate>
            <transactionCoding>
                <transactionFormType>4</transactionFormType>
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                <equitySwapInvolved>0</equitySwapInvolved>
                <footnoteId id="F1"/>
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            <transactionAmounts>
                <transactionShares>
                    <value>59166</value>
                </transactionShares>
                <transactionPricePerShare>
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            </transactionAmounts>
            <exerciseDate>
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            <expirationDate>
                <value>2017-03-03</value>
            </expirationDate>
            <underlyingSecurity>
                <underlyingSecurityTitle>
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        </derivativeTransaction>
        <derivativeTransaction>
            <securityTitle>
                <value>Non-Qualified Stock Option (Right-to-Buy)</value>
            </securityTitle>
            <conversionOrExercisePrice>
                <value>56.50</value>
            </conversionOrExercisePrice>
            <transactionDate>
                <value>2012-04-02</value>
            </transactionDate>
            <deemedExecutionDate></deemedExecutionDate>
            <transactionCoding>
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                <equitySwapInvolved>0</equitySwapInvolved>
                <footnoteId id="F1"/>
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            <transactionAmounts>
                <transactionShares>
                    <value>61747</value>
                </transactionShares>
                <transactionPricePerShare>
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                <transactionAcquiredDisposedCode>
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            <exerciseDate>
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            <expirationDate>
                <value>2018-03-02</value>
            </expirationDate>
            <underlyingSecurity>
                <underlyingSecurityTitle>
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        <derivativeTransaction>
            <securityTitle>
                <value>Non-Qualified Stock Option (Right-to-Buy)</value>
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            <conversionOrExercisePrice>
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            </conversionOrExercisePrice>
            <transactionDate>
                <value>2012-04-02</value>
            </transactionDate>
            <deemedExecutionDate></deemedExecutionDate>
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                <transactionCode>A</transactionCode>
                <equitySwapInvolved>0</equitySwapInvolved>
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            <transactionAmounts>
                <transactionShares>
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                </transactionShares>
                <transactionPricePerShare>
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                <transactionAcquiredDisposedCode>
                    <value>A</value>
                </transactionAcquiredDisposedCode>
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            <exerciseDate>
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            </exerciseDate>
            <expirationDate>
                <value>2019-02-27</value>
            </expirationDate>
            <underlyingSecurity>
                <underlyingSecurityTitle>
                    <value>Express Scripts Holding Company Common Stock</value>
                </underlyingSecurityTitle>
                <underlyingSecurityShares>
                    <value>81780</value>
                </underlyingSecurityShares>
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            <postTransactionAmounts>
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                </sharesOwnedFollowingTransaction>
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            <ownershipNature>
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        <derivativeTransaction>
            <securityTitle>
                <value>Non-Qualified Stock Option (Right-to-Buy)</value>
            </securityTitle>
            <conversionOrExercisePrice>
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            </conversionOrExercisePrice>
            <transactionDate>
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            <deemedExecutionDate></deemedExecutionDate>
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                <transactionCode>A</transactionCode>
                <equitySwapInvolved>0</equitySwapInvolved>
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                <transactionShares>
                    <value>15595</value>
                </transactionShares>
                <transactionPricePerShare>
                    <footnoteId id="F1"/>
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                <transactionAcquiredDisposedCode>
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            <exerciseDate>
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                <underlyingSecurityTitle>
                    <value>Express Scripts Holding Company Common Stock</value>
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                <directOrIndirectOwnership>
                    <value>D</value>
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        </derivativeTransaction>
        <derivativeTransaction>
            <securityTitle>
                <value>Phantom Stock Unit</value>
            </securityTitle>
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                <value>0</value>
            </conversionOrExercisePrice>
            <transactionDate>
                <value>2012-04-02</value>
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                <transactionShares>
                    <value>1253.825</value>
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                    <value>A</value>
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            <exerciseDate>
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            <expirationDate>
                <footnoteId id="F7"/>
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            <underlyingSecurity>
                <underlyingSecurityTitle>
                    <value>Express Scripts Holding Company Common Stock</value>
                </underlyingSecurityTitle>
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                </underlyingSecurityShares>
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                <sharesOwnedFollowingTransaction>
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    </derivativeTable>

    <footnotes>
        <footnote id="F1">Common stock and derivative securities of the Issuer were acquired pursuant to the Agreement and Plan of Merger, dated as of July 20, 2011, as amended on November 7, 2011, by and among Express Scripts, Inc., Medco Health Solutions, Inc., the Issuer, Aristotle Merger Sub, Inc., and Plato Merger Sub, Inc. (the &quot;Merger Agreement&quot;).  Upon closing of the transactions contemplated by the Merger Agreement, Express Scripts, Inc. became a wholly owned subsidiary of the Issuer, and each share of common stock of Express Scripts, Inc. was converted into one share of common stock of the Issuer.  Derivative securities relating to the common stock of Express Scripts, Inc. were converted into derivative securities relating to an equal number of shares of common stock of the Issuer with substantially the same terms and conditions (including vesting schedule and exercise price, if applicable).</footnote>
        <footnote id="F2">Vests in three (3) equal installments of the first three (3) anniversaries of the grant date.</footnote>
        <footnote id="F3">Vests in three (3) equal installments on February 28, 2011, February 28, 2012, and February 28, 2013.</footnote>
        <footnote id="F4">Vests in three (3) equal installments on February 28, 2012, February 28, 2013, and February 28, 2014.</footnote>
        <footnote id="F5">Vests in three (3) equal installments on February 28, 2013, February 28, 2014, and February 28, 2015.</footnote>
        <footnote id="F6">Employee Stock Option, contingent upon consummation of the Medco Merger. Options vest in full on February 28, 2014, provided that the Medco Merger transaction is consummated.</footnote>
        <footnote id="F7">Phantom Stock Units credited under Executive Deferred Compensation Plan.   Upon  distribution  each Phantom Stock Unit converts to one share of Common Stock.  Shares vest three (3) years after the plan year to which such credit relates.</footnote>
    </footnotes>

    <remarks></remarks>

    <ownerSignature>
        <signatureName>Jeffrey Hall</signatureName>
        <signatureDate>2012-04-02</signatureDate>
    </ownerSignature>
</ownershipDocument>
