Background: A systemic and intraventricular polychemotherapy regimen (the Bonn protocol) without radiotherapy resulted in durable responses in 75% of patients <60 years with primary CNS lymphoma (PCNSL), but was complicated by a high rate of Ommaya reservoir infections. Here, the efficacy and toxicity of this regimen without intraventricular treatment was evaluated in PCNSL. Patients and methods: From August 2003 to November 2005, 18 patients with PCNSL <60 years (median age, 53 years) were treated in a phase II trial with a high-dose methotrexate (MTX; cycles 1, 2, 4 and 5) and cytarabine (Ara-C; cycles 3 and 6) based systemic therapy including dexamethasone, vinca-alkaloids, ifosfamide and cyclophosphamide. Results: Study accrual was prematurely stopped in November 2005 due to a high rate of early relapses. Seventeen of 18 patients were assessable for response: Nine (53%) achieved complete response (CR), two (12%) complete response/unconfirmed (CRu) and two (12%) partial response (PR); four (24%) showed progressive disease (PD). One treatment was stopped due to toxicity. Median follow-up was 23 months, median response duration was only 10 months in responding patients, and median time to treatment failure (TTF) was 8 months in the whole group. Median overall survival (OS) has not been reached. Systemic toxicity was mainly hematologic. Conclusions: In PCNSL patients <60 years, polychemotherapy without intraventricular treatment results in a high response rate, but is associated with early relapses in the majority of cases. This is in contrast to the results achieved with the same protocol but with intraventricular treatment.