Treatment of primary central nervous system lymphoma (PCNSL) with high-dose methotrexate-based chemotherapy and whole-brain radiotherapy (WBRT) is associated with high rates of relapse and severe neurotoxicity. In an attempt to improve upon these poor results, we treated 21 patients with PCNSL aged 34-69 years (median 56) with high-dose thiotepa, busulfan, cyclophosphamide (TBC) and autologous stem cell transplant (ASCT) as part of front-line therapy, without WBRT. Patient characteristics included: Karnofsky performance status (KPS) <70% (n = 17), age >60 years (n = 8), deep brain involvement (n = 16). Treatment-induced neurotoxicity was not observed in any of these patients. Currently, 11 of 21 patients (52%) are alive and progression-free at a median follow-up of 60 (7-125) months post-ASCT. Causes of death included progressive PCNSL (n = 4), progressive systemic lymphoma (n = 1), early treatment-related mortality (TRM, n = 3) and two late deaths from pneumonia 3 years post-ASCT. All patients who died of TRM were over 60 years of age and had poor performance status. In conclusion, TBC/ASCT offers potential long-term progression-free survival without neurotoxicity when used as part of upfront therapy for PCNSL. However, efforts to reduce TRM through improved patient selection and possibly through decreased intensity of the TBC regimen for older or less fit patients are recommended.