Background: Central nervous system (CNS) relapse is an infrequent but serious and challenging complication in diffuse large B-cell lymphoma (DLBCL) that carries a dismal prognosis. While several risk factors have been identified to stratify the risk for CNS relapse including the 2015 CNS internal Prognostic index (CNS-IPI), controversy still remains regarding the indication, timing, and method of CNS prophylaxis. The purpose of this study was to determine whether IT-MTX reduced the risk of CNS relapse, as well as treatment related and financial toxicity of CNS prophylaxis. Methods: We performed a single-center, retrospective analysis on a cohort of 192 patients with DLBCL who had received treatment between January 2010- August 2022. Patients were identified by using ICD10 code diagnosis in the electronic medical records system. We included patients of all stages of disease and CNS-IPI scores along with patients with testis, breast, sinus, and bone marrow extranodal involvement. Patients with primary CNS disease and primary mediastinal disease were excluded from the study. Clinical data collected by chart review included age at time of diagnosis, sex, performance status, LDH level, disease stage, number and type of therapies administered including IT-MTX, extranodal involvement, MYC/BCL2/BCL6 translocation status, HIV status, cell of origin (COO), treatment response. Toxicities and complications thought to be associated with IT-MTX prophylaxis were also documented in addition to total costs of treatment for each patient. Patient characteristics were compared using Fisher exact test or Pearson’s chi-square test. Results: In patients with intermediate to high CNS relapse risk (CNS-IPI 2-5) IT-MTX did not reduce the 1 year risk of CNS relapse (RR 1.1296, 95% CI 0.1933 to 6.6012, P = 0.08924). The median time to CNS relapse was longer in patients who had received IT-MTX (13.5 months) vs those who did not (7 months). Thirty eight (52.8%) patients reported adverse side effects of any kind as a result of IT-MTX administration, with 23.6% of patients developing grade 2-3 adverse events. The average cost for CNS-prophylaxis was estimated to be approximately $8,059.04 over a patient’s treatment course, but as high as $20,140. Conclusions: In conclusion, our study highlights the necessity to develop improved standardized guidelines for use of CNS prophylaxis in patients with DLBCL. The results from our retrospective study add to the growing body of literature showing IT-MTX has limited and potentially transient effectiveness in preventing CNS relapse. Given the high rate of side effects and significant cost of IT-MTX, we recommend that clinicians carefully consider the risks and benefits of prophylaxis before prescribing IT-MTX for CNS-prophylaxis.