Primary central nervous system lymphoma (PCNSL) in the immunocompetent patient reaches a peak incidence in the sixth and seventh decades of life. This retrospective study reviewed the efficacy and tolerability of high-dose methotrexate (HDMTX) in an elderly patient population. Between May 1995 and September 1998, ten consecutive elderly patients with histologically proven PCNSL were treated with HDMTX. The median age was 72.5 years and eight patients (80%) were older than 70 years. HDMTX was well tolerated with no episodes of grade 4 toxicity nor febrile neutropenia. Toxicity included grade 3 nausea (1), grade 2 mucositis (2), and grade 2 asymptomatic elevation of liver transaminases (2). Grade 1 toxicity occurred in three patients with nausea, diarrhea, and mild reversible elevation in serum creatinine in one patient each. Six patients had a complete response and three patients achieved a partial response, giving an overall response rate of 90% (95% confidence interval, 56%-100%). The median overall survival for the cohort was 36 months (range 4-43 months). In summary, HDMTX is well tolerated in this elderly population with PCNSL and achieves response rates and median survival comparable with other chemotherapy or radiotherapy regimens.