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Central nervous system (CNS) relapse affects 5% of diffuse large B-cell lymphoma (DLBCL) patients and portends a poor prognosis. Prophylactic intravenous high-dose methotrexate (HD-MTX) is frequently employed to reduce this risk, but there is limited evidence supporting this practice. We conducted a multicenter retrospective study to determine the CNS relapse risk with HD-MTX in DLBCL patients aged 18-70 years treated in Alberta, Canada between 2012 and 2019. Provincial guidelines recommended HD-MTX for patients at high-risk of CNS rel