BACKGROUND: We aimed to determine safety and efficacy of rituximab (R) in combination with repetitive high-dose therapy (HDT) as primary treatment for diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: Patients aged 18-60 years and elevated lactate dehydrogenase were treated with four cycles of MegaCHOEP and transplantation of autologous stem cells after cycles 2, 3 and 4. Rituximab (375 mg/m²) was given before each cycle and 12 and 33 days after start of the last cycle of chemotherapy. Sixty-four patients given R-MegaCHOEP were compared with 29 patients who had received identical treatment without rituximab. RESULTS: Overall survival (OS) and event-free survival (EFS) after 3 years were significantly improved in patients treated with R-MegaCHOEP (OS: 78.7% versus 55.0%, P = 0.045; EFS: 72.7% versus 47.2%, P = 0.013). In a Cox regression model adjusted for performance status and stage, relative risk of treatment failure was lower (relative risk 0.5, P = 0.041) and OS was better (relative risk 0.4, P = 0.054) for patients given R-MegaCHOEP. Grade 3/4 infections were more frequent in the R-MegaCHOEP group (18.5% versus 6.0%, P = 0.003). CONCLUSIONS: The addition of rituximab to MegaCHOEP significantly improved outcome in young patients with high-risk DLBCL. The higher incidence of grade 3/4 infections needs consideration when rituximab and HDT regimens are combined.