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The prognosis of diffuse large B-cell lymphoma (DLBCL) patients depends on lymphoma- and patient-related risk factors and is best estimated by the international prognostic index (IPI). The aim of the study was to determine whether the average relative dose intensity (ARDI) of an anthracycline-containing regimen could predict DLBCL outcome independently from the IPI. We analyzed 223 white Caucasian DLBCL patients who completed at least four cycles of first-line immunochemotherapy with rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisone (R-CHOP). The ARDI was calculated by specially developed software in each individual patient, simultaneously with the chemotherapy prescription, which instantly revealed all causes of its decrease. The relevance of the ARDI for progression-free/overall survival (PFS/OS) was evaluated. Prolonged intervals between cycles of immunochemotherapy-the most common cause of decreased ARDI (49.3%, 110/223)-were due to neutropenia (absolute neutrophil count <1.0 × 10 9 /L) and infections. Reductions in cytostatic doses were observed in 19.7% (44/223) of patients, mainly as the consequence of cardiotoxicity (23/223, 10.3%). The OS varied significantly when the ARDI was >90% (P < 0.00001). Multivariate analysis confirmed that an ARDI>90% was an IPI-independent predictor of prolonged PFS (HR = 0.31; 95%CI: 0.20-0.47; P < 0.00001) and OS (HR = 0.32; 95%CI: 0.21-0.48; P < 0.00001). With an analytic tool allowing real-time ARDI assessment, it was possible to maintain an ARDI above 90% in 161 of 223 patients (72%). DLBCL patients with an ARDI >90% have significantly better outcome regardless of the IPI; therefore, our official recommendation is an adequate dose density through efficient neutropenia prophylaxis and cardiac protection., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)