CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is characterized by poor prognosis and a high frequency of central nervous system relapse after standard immunochemotherapy. We conducted a phase 2 study to investigate the efficacy and safety of dose-adjusted (DA)- EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) combined with high-dose methotrexate (HD-MTX) in newly diagnosed patients with CD5+ DLBCL. Previously untreated patients with stage II to IV CD5+ DLBCL according to the 2008 WHO classification were eligible. Four cycles of DA-EPOCH-R followed by 2 cycles of HD-MTX and 4 additional cycles of DA-EPOCH-R (DA-EPOCH-R/HD-MTX) were planned as the protocol treatment. The primary endpoint was 2-year progression-free survival. Between September 25, 2012 and November 11, 2015, we enrolled 47 evaluable patients. Forty-five (96%) patients completed the protocol treatment. There were no deviations or violations in the DA-EPOCH-R dose levels. The complete response rate was 91%, and the overall response rate was 94%. At a median follow-up of 3.1 years (range, 2.0-4.9), the 2-year progression-free survival was 79% (95% confidence interval, 64-88). The 2-year overall survival was 89% (95% confidence interval, 76-95). Toxicity included grade 4 neutropenia in 46 (98%) patients, grade 4 thrombocytopenia 12 (26%) patients, and febrile neutropenia in 31 (66%) patients. No treatment-related death was noted during the study. DA-EPOCH-R/HD-MTX might be a first-line therapy option for stage II-IV CD5+ DLBCL and warrants further investigation.