PURPOSE: To assess, in a multi-institutional setting, the impact on relapse, survival, and toxicity of adding two cycles of intravenous methotrexate to cranial irradiation for immunocompetent patients with primary CNS lymphoma. PATIENTS AND METHODS: Forty-six patients with a median age of 58 years and Eastern Cooperative Oncology Group performance status 0 to 3 were entered onto this phase II study. The protocol consisted of methotrexate 1 g/m² on days 1 and 8 followed by cranial irradiation on day 15. A whole-brain dose of 45 Gy was followed by a boost of 5.4 Gy. Intrathecal chemotherapy and spinal irradiation were given only to patients for whom cytologic examination of CSF was positive for CNS lymphoma. The median follow-up time was 36 months, with a minimum potential follow-up of 12 months. RESULTS: Median survival was 33 months, with 2-year probability of survival 62% ± 15% (95% confidence interval). Twenty patients have relapsed. The predominant site of relapse was the brain. Neither performance status nor age was found to influence survival. Six patients developed a dementing illness at a median of 16 months after treatment, and three of these died as a consequence. CONCLUSION: A brief course of intravenous methotrexate before cranial irradiation is associated with 2-year and median survival rates superior to those reported for radiotherapy alone and similar to more intensive combined-modality regimens. Neurotoxicity remains an important competing risk for these patients.