Male gender was recently reported as an adverse prognostic factor in patients with diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). We conducted a retrospective study of adult patients with DLBCL initially treated with rituximab containing regimens between 2001 and 2007. Patients were identified from the clinical archives of 43 Italian and Brazilian institutions. The principal endpoint was overall survival (OS). One thousand seven hundred and ninety-three patients were fully eligible for the study. Thirty-eight percent, 27%, 22% and 12% of patients had an International Prognostic Index (IPI) score of 0-1, 2, 3 and 4-5, respectively; 53% were males. After a median follow-up of 36 months (1-106), the 5-year OS was 76% (95% confidence interval 74-78%). In univariate analysis, male gender was an adverse prognostic factor with a hazard ratio of 1.52. In multivariate analysis, when adjusted by IPI, again gender maintained its prognostic relevance, showing an independent additive effect. In conclusion, in patients with DLBCL treated with rituximab containing regimens, gender may increase the predictive power of the IPI. Based on these results, given possible differences in blood clearance of rituximab between males and females, the benefit of higher doses of rituximab in males should be explored.