Key Clinical Message: Optimized treatments for relapsed isolated CNS lymphoma (RI-SCNSL) remains under investigation. Temozolomide combination-based therapy, which is often used in glioblastoma may be used as potential treatment in RI-SCNSL., Abstract: One of the most common types of non-Hodgkin lymphoma (NHL) is diffuse large B-cell lymphoma (DLBCL). Despite advances in treatment, relapsed isolated CNS lymphoma (RI-SCNSL) from DLBCL remains an issue. The optimal approach in RI-SCNSL remains an area of active investigation as currently there is no high level of evidence for the treatments due to lack of randomized studies. In this case report, we present a DLBCL patient with CNS recurrence treated radiotherapy and intrathecal methotrexate (MTX) followed by intravenous high-dose MTX, rituximab, and temozolomide. To the best of our knowledge, this is the first case report describing RI-SCNSL treated with the regiments above which also include temozolomide which is used for glioblastoma., Competing Interests: All authors declare no conflict of interest., (© 2024 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)