Nine patients with primary central nervous system lymphoma (PCNSL) were evaluated in a protocol of systemic and intrathecal chemotherapy and radiation therapy (RT). The median survival was 30 months; median time to recurrence was 14 months. Leukoencephalopathy developed in 7/9 patients, 6-12 months after combination therapy. 5/9 patients worsened cognitively 6-14 months after therapy; all developed leukoencephalopathy. The four patients who had an initial positive cytology or delayed CSF outflow did not worsen cognitively, although two developed leukoencephalopathy. The combination of chemotherapy and RT improves survival of patients with PCNSL; however, leukoencephalopathy and cognitive changes are frequent.