This study analyzed retrospectively the clinical efficacy of combined therapy consisting of high-dose methotrexate (MTX), administered at a dose of 4 g/m2 every 2 weeks (maximum of 4 courses), followed by whole-brain irradiation for newly diagnosed primary central nervous system lymphoma (PCNSL) patients. Fifteen patients (median age: 59 years old; range: 26-79) were diagnosed by histological examinations or imaging techniques in our hospital. Of 15 patients, 12 (6: complete response; 6: partial response) achieved objective response, and the response rate was 80% (95% CI, 51.9-95.7%). The median follow-up time was 20 (range: 3-81) months, and the 3-year survival rate was 76%. The overall survival time was 71 months (95% CI, 23. 7-118.3 months), and the progression free survival was 15 months (95% CI, 0-43.8 months). The major toxicity (grade>or=3) of high-dose MTX included cytopenia (20%), acute respiratory distress syndrome (6.7%), and liver damage (6.7%). No patient evidenced complicated leukoencephalopathy in the follow-up time. The combined therapy of high-dose MTX followed by whole-brain irradiation showed a substantial antitumor efficacy in PCNSL patients. Prospective studies are required to determine the suitable treatment schedule for MTX and irradiation.