<?xml version="1.0" encoding="UTF-8"?>
<edgarSubmission xmlns="http://www.sec.gov/edgar/thirteenffiler" xmlns:com="http://www.sec.gov/edgar/common">
  <schemaVersion>X0202</schemaVersion>
  <headerData>
    <submissionType>13F-HR</submissionType>
    <filerInfo>
      <liveTestFlag>LIVE</liveTestFlag>
      <flags>
        <confirmingCopyFlag>false</confirmingCopyFlag>
        <returnCopyFlag>false</returnCopyFlag>
        <overrideInternetFlag>false</overrideInternetFlag>
      </flags>
      <filer>
        <credentials>
          <cik>0001496201</cik>
          <ccc>XXXXXXXX</ccc>
        </credentials>
      </filer>
      <periodOfReport>09-30-2025</periodOfReport>
    </filerInfo>
  </headerData>
  <formData>
    <coverPage>
      <reportCalendarOrQuarter>09-30-2025</reportCalendarOrQuarter>
      <filingManager>
        <name>SPHERA FUNDS MANAGEMENT LTD.</name>
        <address>
          <com:street1>4 ITZHAK SADE BUILDING A</com:street1>
          <com:street2>29TH FLOOR</com:street2>
          <com:city>TEL AVIV</com:city>
          <com:stateOrCountry>L3</com:stateOrCountry>
          <com:zipCode>6777520</com:zipCode>
        </address>
      </filingManager>
      <reportType>13F HOLDINGS REPORT</reportType>
      <form13FFileNumber>028-15863</form13FFileNumber>
      <crdNumber>000312614</crdNumber>
      <secFileNumber>802-120694</secFileNumber>
      <provideInfoForInstruction5>Y</provideInfoForInstruction5>
      <additionalInformation>Investment discretion with regard to a portion of the securities reported herein is exercised by Sphera Global Healthcare Management L.P. (the "Management Company"). The Management Company is managed, controlled, and operated by its general partner, Sphera Global Healthcare GP Ltd. (the "General Partner"), the shares of which are owned 90% by Sphera Funds Management Ltd. ("SFML"). SFML is entitled to appoint the members of the board of directors of the General Partner (the "Board of Directors"), and therefore may be deemed to control the General Partner and Management Company. This Form 13F shall not be construed as an admission by SFML, the General Partner, or the Management Company that it is the beneficial owner of any of the securities covered by this Form 13F, and each of SFML, the General Partner, and the Management Company disclaim beneficial ownership of any such securities. Per informal guidance received from the Division of Investment Management, section 13(f) securities that are dual listed on a U.S. stock exchange and the Tel Aviv Stock Exchange were included in this Form 13F only if they were purchased in the U.S.</additionalInformation>
    </coverPage>
    <signatureBlock>
      <name>Oshrat Levi</name>
      <title>Chief Financial Officer</title>
      <phone>972 3 6845617</phone>
      <signature>Oshrat Levi</signature>
      <city>Tel Aviv</city>
      <stateOrCountry>L3</stateOrCountry>
      <signatureDate>11-14-2025</signatureDate>
    </signatureBlock>
    <summaryPage>
      <otherIncludedManagersCount>2</otherIncludedManagersCount>
      <tableEntryTotal>115</tableEntryTotal>
      <tableValueTotal>474069298</tableValueTotal>
      <isConfidentialOmitted>false</isConfidentialOmitted>
      <otherManagers2Info>
        <otherManager2>
          <sequenceNumber>1</sequenceNumber>
          <otherManager>
            <cik>0001599854</cik>
            <form13FFileNumber>028-15865</form13FFileNumber>
            <crdNumber>000172608</crdNumber>
            <secFileNumber>802-127045</secFileNumber>
            <name>Sphera Global Healthcare Management LP</name>
          </otherManager>
        </otherManager2>
        <otherManager2>
          <sequenceNumber>2</sequenceNumber>
          <otherManager>
            <cik>0001599855</cik>
            <form13FFileNumber>028-15864</form13FFileNumber>
            <name>Sphera Global Healthcare GP Ltd.</name>
          </otherManager>
        </otherManager2>
      </otherManagers2Info>
    </summaryPage>
  </formData>
</edgarSubmission>
