Background: Chemotherapy with high-dose methotrexate is the conventional approach to treat primary CNS lymphomas, but superiority of polychemotherapy compared with high-dose methotrexate alone is unproven. We assessed the effect of adding high-dose cytarabine to methotrexate in patients with newly diagnosed primary CNS lymphoma. Methods: This open, randomised, phase 2 trial was undertaken in 24 centres in six countries. 79 patients with non-Hodgkin lymphoma exclusively localised into the CNS, cranial nerves, or eyes, aged 18-75 years, and with Eastern Cooperative Oncology Group performance status of 3 or lower and measurable disease were centrally randomly assigned by computer to receive four courses of either methotrexate 3·5 g/m2 on day 1 (n=40) or methotrexate 3·5 g/m2 on day 1 plus cytarabine 2 g/m2 twice a day on days 2-3 (n=39). Both regimens were administered every 3 weeks and were followed by whole-brain irradiation. The primary endpoint was complete remission rate after chemotherapy. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00210314. Findings: All randomly assigned participants were analysed. After chemotherapy, seven patients given methotrexate and 18 given methotrexate plus cytarabine achieved a complete remission, with a complete remission rate of 18% (95% CI 6-30) and 46% (31-61), respectively, (p=0·006). Nine patients receiving methotrexate and nine receiving methotrexate plus cytarabine achieved a partial response, with an overall response rate of 40% (25-55) and 69% (55-83), respectively, (p=0·009). Grade 3-4 haematological toxicity was more common in the methotrexate plus cytarabine group than in the methotrexate group (36 [92%] vs six [15%]). Four patients died of toxic effects (three vs one). Interpretation: In patients aged 75 years and younger with primary CNS lymphoma, the addition of high-dose cytarabine to high-dose methotrexate provides improved outcome with acceptable toxicity compared with high-dose methotrexate alone. Funding: Swiss Cancer League. © 2009 Elsevier Ltd. All rights reserved.