Purpose: Over the past decade, high-dose methotrexate has emerged as the single most effective agent in the initial treatment of primary nervous system lymphoma. However, the majority of patients who respond initially to treatment relapse. The optimal management of these patients has not been determined. We performed a multicenter, retrospective study of high-dose methotrexate in patients with relapsed central nervous system lymphoma. Experimental Design: Patients with relapsed disease were eligible if they achieved a complete response to initial treatment with methotrexate-based chemotherapy or received methotrexate after gross total resection of interstitial radiation. All of the patients were retreated with a regimen containing high-dose methotrexate (≥3 g/m2). Results: Twenty-two patients with a median age of 58 years were included in the study. Overall response rates were 91% to first salvage (20 of 22 patients) and 100% to second salvage (4 of 4 patients). Median survival was 61.9 months after first relapse (95% confidence interval, 42.1-∞) and 91.9 months overall (95% confidence interval, 47.2-∞). Toxicity was primarily hematologic with 10 episodes of grade 3 or 4 toxicity during 566 cycles of chemotherapy. Conclusions: These results indicate that high-dose methotrexate remains effective for relapsed central nervous system lymphoma in patients who initially respond to methotrexate and raise the possibility of deferring more toxic salvage regimens in this select group of patients.