Background: High-dose methotrexate (HD-MTX) is administered as prophylaxis for central nervous system (CNS) relapse in Diffuse Large B Cell Lymphoma (DLBCL). It is traditionally administered in an inpatient setting due to its complex supportive care regimen. We developed an outpatient protocol and evaluated the safety of this approach. Methods: In 2019 a multidisciplinary team at Kingston Health Sciences Centre developed an outpatient HD-MTX protocol for CNS prophylaxis in DLBCL. Select eligible patients received their HD-MTX infusion in the day unit and returned daily for bloodwork and monitoring. Leucovorin and continuous intravenous hydration were administered via ambulatory infusion pumps. A single centre retrospective cohort analysis was conducted on all patients who received outpatient HD-MTX. These patients were compared to a historical control group who underwent inpatient HD-MTX and who would have met outpatient eligibility criteria. To evaluate the safety of the outpatient protocol we compared the risk of significant toxicity, defined as an elevation in serum creatinine or oral mucositis of grade III or higher, or development of febrile neutropenia. We also evaluated the time to MTX serum clearance, patient admissions and delays of subsequent chemotherapy cycles. Results: From June 2017 to March 2021, 6 outpatients undergoing 14 HD-MTX cycles and 13 inpatients undergoing 28 cycles were evaluated. Significant toxicity occurred in one outpatient cycle compared to five inpatient cycles (7.1% vs 17.9%, p = 0.79). Average time to MTX clearance was 4.1 days for outpatients and 3.5 days for inpatients (p = 0.013). Only one outpatient was admitted to hospital, resulting in an average length of hospital stay of 0.5 days for outpatients compared to 4.96 days for inpatients. There was no significant difference in the need to delay a subsequent cycle of chemotherapy. Conclusions: Outpatient administration of HD-MTX can be administered safely and effectively as CNS prophylaxis in select patients with DLBCL.