Purpose: We developed and evaluated a regimen including fotemustine, teniposide and dexamethasone (FTD) for treating patients with central nervous system (CNS) lymphoma based on pharmacokinetic properties of individual agents and in combination. Patients and Methods: In a comparison study, 8 patients with primary CNS lymphoma (PCNSL) and 8 with secondary CNS lymphoma (SCNSL) were treated with FTD (comprising fotemustine 100 mg/m2, 1h infusion, day 1; teniposide 60 mg/m2, >0.5 h infusion, on day 2, 3, 4; dexamethasone 40 mg, 1h infusion, on day 1, 2, 3, 4 and 5; and methotrexate 12 mg, cytosine arabinoside 50 mg plus dexamethasone 5 mg intrathecally, on day 2 and 7). Cycles were repeated every 3 weeks. After response assessment, patients received whole brain radiotherapy. Results: Of the 8 PCNSL patients, 4 (50%) achieved CR and 3 (38%) PR, an overall response rate of 88%. Four patients (50%) were in continuing remission at the end of this study after a median follow-up of 30 months (range 10 to 56 months). Of the 8 SCNSL patients the overall response rate was 63% (CR+PR: 38%+25%). All responses were achievable with predictable toxicity mainly reflecting reversible myelosuppression. Conclusion: This study suggests that FTD could be an effective treatment for CNS lymphoma, and is worthy of further evaluation.