The treatment of primary central nervous system lymphoma with chemotherapy prior to whole-brain radiation therapy (WBRT) has improved outcome considerably in this previously fatal disease. Complete or partial responses to intravenous methotrexate (3.5 gm/sq m with leucovorin rescue every 3 weeks for two to four cycles) were seen in 12 of 13 patients originally treated. A total of 25 patients (including the original 13) have now been treated with one to six cycles of methotrexate every 10 to 21 days prior to WBRT. Twenty-two had partial or complete responses, with a median duration of response of 32 months. Median survival time was 33 months (42.5 months in those responding to therapy). Nine patients are alive and without evidence of disease 9 to 122 months following therapy. Acute and long-term toxicities were minimal. Systemic methotrexate administration prior to WBRT is well tolerated and produces long-term survival.