Purpose Dose‐adjusted EPOCH and rituximab (DA‐EPOCH‐R) is a regimen used for the treatment of high‐risk diffuse large B‐cell lymphoma (DLBCL) designed to overcome resistance to standard R‐CHOP by combining prolonged exposure of lymphoma cells to cytotoxic agents and dose‐adjustment based on toxicity. Data on outcomes of older patients are scarce. Patients and Methods We collected data on patients with newly diagnosed high‐risk DLBCL older than 60 years treated with DA‐EPOCH‐R. High‐risk patients were defined by the age‐adjusted international prognostic index score 2 or 3. Results A total of 120 patients were included. Median age was 69 years (range 60–82). Response rate was 74%; with 59% complete responses. Dose of DA‐EPOCH‐R was escalated in 50 patients (42%). Three‐year progression‐free survival (PFS) and overall survival (OS) was 53% and 58%, respectively, with treatment‐related mortality (TRM) of 13%. In univariate analysis, favorable prognostic factors were performance status (PS) (0–2 vs. 3–4), age (<70 vs. ≥70 years), and center. In multivariate analysis, PS and center retained prognostic significance. Patients with PS 0–2 had 3‐year PFS and OS of 58% and 64%, respectively, with TRM of 6%. Conclusion DA‐EPOCH‐R is efficacious in sufficiently fit older high‐risk DLBCL patients. Patients with poor PS have unacceptable toxicity and require less intensive therapy.