A specific prognostication of hepatitis C virus positive diffuse large B cell lymphomas is not available. At this purpose, the Fondazione Italiana Linfomi carried out a multicenter retrospective study on a large consecutive series of patients with hepatitis C virus-associated diffuse large B cell lymphoma, to evaluate the prognostic impact of clinical and virological features and to develop a specific prognostic score for this subset of patients. All prognostic evaluations were performed on 535 patients treated with an anthracycline-based induction regimen (with rituximab in 255 cases). Severe hepatotoxicity was observed in 14% of patients. The use of rituximab was not associated with increased rate of severe hepatotoxicity. Three-year overall survival and progression-free survival were 71% and 55%, respectively. At multivariate analysis, ECOG performance status ≥2, serum albumin <3.5 g/dl and HCV-RNA viral load >1000 KIU/ml retained prognostic significance. We combined these 3 factors in a new HCV Prognostic Score able to discriminate 3 risk categories with different overall and progression-free survival (low=0; intermediate=1; high-risk ≥2 factors, p<0.001). This score retained prognostic value in the subgroups of patients treated with and without rituximab (p<0.001). The new score performed better than International Prognostic Index at multivariate analysis and Harrel C-statistic. With the use of three readily available factors (performance status, albumin level and HCV-RNA viral load), the new HCV Prognostic Score is able to identify three risk-categories with different survival, and may be a useful tool to predict the outcome of hepatitis C virus-associated diffuse-large B cell-lymphoma.