Outcomes for patients with high-risk diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP chemotherapy are suboptimal but, to date, no alternative regimen has been shown to improve survival rates. This phase 2 trial aimed to assess the efficacy of a Burkitt-like approach for high-risk DLBCL using the dose-intense R-CODOX-M/R-IVAC regimen.Eligible pts were aged 18-65 years with stage II-IV untreated DLBCL and an International Prognostic Index (IPI) score of 3-5. Patients received alternating cycles of CODOX-M and IVAC (cyclophosphamide, vincristine, doxorubicin and high-dose methotrexate [CODOX-M] alternating with ifosfamide, etoposide and high-dose cytarabine [IVAC]) chemotherapy plus 8 doses of rituximab. Response was assessed by CT after completing all 4 cycles of chemotherapy. The primary endpoint was 2-year progression-free survival (PFS).111 eligible patients were registered; median age was 50 years, IPI score was 3 (60.4%) or 4-5 (39.6%), 54% had a performance status ≥2 and 9% had central nervous system involvement. 85 patients (76.6%) completed all 4 cycles of chemotherapy. There were 5 treatment-related deaths (4.3%), all in patients with performance status of 3 and aged >50 years. Two-year PFS for the whole cohort was 67.9% (90% CI: 59.9 - 74.6) and 2-year overall survival was 76.0% (90% CI: 68.5 - 82.0). The ability to tolerate and complete treatment was lower in patients with PS ≥2 who were aged >50 years, where 2-year PFS was 43.5% (90% CI: 27.9 - 58.0).This trial demonstrates that R-CODOX-M/R-IVAC is a feasible and effective regimen for the treatment of younger and/or fit patients with high-risk DLBCL. These encouraging survival rates demonstrate that this regimen warrants further investigation against standard of care.