The National Comprehensive Cancer Network (NCCN) recommends a regimen of rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP) with methotrexate (MTX) given at ≥3 g/m² for stage IV diffuse large B-cell lymphoma with parenchymal involvement. Tumor lysis syndrome (TLS) may occur after initiation of treatment. MTX, though beneficial, may induce toxicity, especially in elderly patients with comorbidities. This paper discusses a case of 74-year-old female with secondary central nervous system lymphoma with multiple comorbidities and high risk for TLS given a modified schedule of R-CHOP and a lower dose of MTX at 2–2.5 g/m² with a good treatment response. This paper aims to contribute additional information on optimal treatment for this disease.