The object of this study was to assess the estimation of 2- and 5-year overall survival and tumor response and the frequency and severity of treatment morbidity with a modified ProMACE-MOPP hybrid protocol in patients with primary CNS lymphoma (PCNSL). Thirty-two immunocompetent patients were treated with a regimen of pirarubicin, cyclophosphamide, etoposide, vincristine, and methotrexate (500 mg/m(2)) administered in 21-day cycles. Intraventricular 10 mg of methotrexate was given for eight cycles once a week. Patients received 20 Gy of whole brain radiotherapy after three cycles of chemotherapy. A single cycle of chemotherapy was repeated every 4 months for 2 years. Older patients (aged >60) received a reduced dose of chemotherapeutic agents. Eighteen patients were followed up with neuroimaging and neuropsychological assessments for evidence of CNS toxicity. Sixteen patients completed the regimen as planned. The response rate was 87.5% after the initial chemoradiotherapy. The cumulative survival and progression-free survival rates at 5 years were 56 and 31%, respectively. The median survival time was 68 months. The median progression-free survival time was 39 months. Toxicity included grade 3 or 4 leukopenia in 33% of the cycles administered. There were eight grade 3 or 4 pulmonary toxicities. There were three deaths during chemotherapy: one as a result of sepsis and two of pneumonitis. Three patients (25%) experienced delayed neurologic toxicity while on the complete regimen. Maintaining the dose of methotrexate while adding chemotherapeutic agents improved disease control and overall survival in patients with PCNSL, but early toxicity and delayed neurotoxicity are still a risk of this approach.