Burkitt leukemia/lymphoma (BL) and high-grade B-cell lymphoma (HGBL) have a high incidence of central nervous system (CNS) involvement, which is associated with poor prognosis. The Hyper-CVAD-R regimen includes systemic and intrathecal CNS-directed therapy to treat and prevent CNS disease. We report herein the long-term safety and efficacy of the Hyper-CVAD-R regimen in adults with BL and HGBL, focusing on its efficacy to prevent CNS relapse. Among 79 adults (54 BL, 25 HGBL), the median age was 44 years (25% ≥ 60 years old), 73% had bone marrow (BM) involvement and 28% had CNS involvement. The complete remission rate was 91% (BL 96%; HGBCL 79%; p=0.16). The 5-year relapse-free survival (RFS) and overall survival (OS) rates were 58% and 52%, respectively. The cumulative incidence of relapse (CIR) was 21% (BL 14%; HGBCL 37%, p=0.06) and was associated with baseline BM (27% vs 0%; p=0.02) and CNS (42% vs 12%; p<0.01) involvement. In multivariate analyses, age and CNS involvement were independent predictors for OS and RFS. The 5-year CNS CIR was 6% (BL 4%; HGBL 11%, p=0.31); 16% with baseline CNS involvement (p=0.03). Our data support the use of Hyper-CVAD-R in preventing CNS relapse, especially among high-risk patients with BM or CNS involvement.