Background: The current institutional standard for treatment of patients with newly-diagnosed primary CNS lymphomas (PCNSL) at Johns Hopkins Hospital (JHH) consists of treatment with high-dose methotrexate plus rituximab (hd-MTX/R) every 2 weeks until complete response (CR), progression or unacceptable toxicities. Once CR is achieved, this is followed by monthly treatments for a total of up to one year for consolidation. Prior to 2008, the institutional standard had been treatment with hd-MTX alone. The benefit of adding rituximab to hd-MTX has not been formally evaluated. Methods: This is a retrospective study of HIV-negative adult patients with newly-diagnosed PCNSL treated at JHH with either hd-MTX or hd-MTX/R as initial therapy. Patients were identified using the cancer center registry (1995-2012) and were included if they had received at least one cycle of therapy (intention-to-treat). Primary objectives were CR rate (patients with sufficient imaging data; centrally reviewed) and overall survival (OS, all patients included). Results: A total of 81 patients were analyzed (median age of 65 yrs; 52% male). 54 patients received hd-MTX alone (median age, 65 yrs) and 27 patients received hd-MTX/R (median age, 66 yrs). 37 and 24 patients in the two groups were evaluable for response, respectively. Among these, the CR rate was 51% in patients treated with hd-MTX alone (overall response rate, ORR, 76%) and 79% in patients treated with hd-MTX/R (ORR 96%). The median number of cycles to CR was 5 and 4.5, respectively. Median OS among all patients (both groups combined) was 26 months (95% CI: 11-44). Conclusions: These data show potential clinical benefit from the addition of rituximab to hd-MTX for newly diagnosed patients with PCNSL based on a higher CR rate. Analysis of OS benefit between patients treated with hd-MTX and hd-MTX/R is pending maturation of further survival data.