OBJECTIVE:This is the final report of a phase III randomized study to evaluate whole-brain radiotherapy (WBRT) in primary therapy of primary CNS lymphoma (PCNSL) after a median follow-up of 81.2 months. METHODS:Patients with newly diagnosed PCNSL were randomized to high-dose methotrexate (HDMTX)–based chemotherapy alone or followed by WBRT. We hypothesized that the omission of WBRT would not compromise overall survival (OS; primary endpoint), using a noninferiority design with a margin of 0.9. RESULTS:In the per-protocol population (n = 320), WBRT nonsignificantly prolonged progression-free survival (PFS) (median 18.2 vs 11.9 months, hazard ratio HR 0.83 95% confidence interval (CI) 0.65–1.06, p = 0.14) and significantly PFS from last HDMTX (25.5 vs 12.0 months, HR 0.65 95% CI 0.5–0.83, p = 0.001), but without OS prolongation (35.6 vs 37.1 months, HR 1.03 95% CI 0.79–1.35, p = 0.82). In the intent-to-treat population (n = 410), there was a prolongation by WBRT of both PFS (15.4 vs 9.9 months, HR 0.79 95% CI 0.64–0.98, p = 0.034) and PFS from last HDMTX (19.4 vs 11.9 months, HR 0.72 95% CI 0.58–0.89, p = 0.003), but not of OS (32.4 vs 36.1 months, HR 0.98 95% CI 0.79–1.26, p = 0.98). CONCLUSION:Although the statistical proof of noninferiority regarding OS was not given, our results suggest no worsening of OS without WBRT in primary therapy of PCNSL. CLASSIFICATION OF EVIDENCE:This study provides Class II evidence that in PCNSL HDMTX-based chemotherapy followed by WBRT does not significantly increase survival compared to chemotherapy alone. The study lacked the precision to exclude an important survival benefit or harm from WBRT.