The addition of high-dose methotrexate (HD-MTX) to whole-brain radiation therapy (WBRT) has improved the survival of patients with primary central nervous system lymphoma (PCNSL). However, combined therapy is associated with increased neurotoxicity. In an effort to limit this toxicity, we treated a series of non-immunocompromised patients with HDMVP, a HD-MTX based regimen, with deferral of WBRT until progression. Twenty-three patients were treated with the HDMVP regimen consisting of MTX, vincristine, and procarbazine. The mean age at diagnosis was 60.9 years (range 45-79 years). The overall response rate was 65% (14 complete responses and one partial response). For patients achieving an initial response with HDMVP the median response duration was 40.4 months (95% confidence interval [CI] 19.5-61.3). The median progression-free survival was 4.6 months (95% CI 0.0-20.4) and median overall survival was 41.4 months (95% CI 0.0-95.5). Fourteen patients received WBRT for relapsed or progressive disease. The conclusion of this trial is that HDVMP results in good initial response rates but only moderate disease control. Ultimately the majority of the patients in this series required WBRT for salvage treatment, potentially enabling a delay in treatment-associated neurotoxicity.