Abstract Background Studies on the efficacy of rituximab in Primary CNS Lymphoma (PCNSL) reported conflicting results. Our international randomized phase III study showed that the addition of rituximab to high-dose methotrexate, BCNU, teniposide and prednisolone (MBVP) in PCNSL was not efficacious on the short-term. Here we present long-term results after a median follow-up of 82.3 months. Methods 199 eligible newly-diagnosed, non-immunocompromised patients with PCNSL aged 18-70 years with WHO performance status 0-3 were randomized between treatment with MBVP chemotherapy with or without rituximab, followed by high-dose cytarabine consolidation in responding patients, and reduced-dose WBRT in patients aged ≤60 years. Event-free survival was the primary endpoint. Overall survival rate, neurocognitive functioning (NCF), and health-related quality of life (HRQoL) were additionally assessed, with the IPCG test battery, EORTC QLQ-C30 and QLQ-BN20 questionnaires, respectively. Results For event-free survival, the hazard ratio was 0.85, 95% confidence interval 0.61-1.18, p=0.33. Overall survival rate at 5 years for MBVP and R-MBVP was 49% (39-59) and 53% (43-63) respectively. In total, 64 patients died in the MBVP arm and 55 in the R-MBVP arm, of which 69% due to PCNSL. At group level, all domains of NCF and HRQoL improved to a clinically relevant extent after treatment initiation, and remained stable thereafter up to 60 months of follow-up, except for motor speed which deteriorated between 24 and 60 months. Although fatigue improved initially, high levels persisted in the long-term. Conclusion Long-term follow-up confirms lack of added value of rituximab in addition to MBVP and HD-cytarabine for PCNSL.