In diffuse large B-cell lymphoma (DLBCL), the combination of rituximab and CHOP (cyclophosphamide, doxorubicine, vincristine, prednisone; R-CHOP) has been shown to be more effective than CHOP for the treatment of elderly patients. Bcl-2 protein expression has been associated with poor prognosis in patients with DLBCL. To establish whether or not rituximab reduces bcl-2-associated treatment failure, we studied bcl-2 protein expression and clinical outcome in patients included in the Groupe d'Etude des Lymphomes de l'Adulte LNH-98-5 trial. Patients between 60 and 80 years of age were randomized to receive 8 cycles of either CHOP or R-CHOP every 3 weeks. Of the 399 patients included, 292 with histologically proven DLBCL had material available for bcl-2 study. Tumors were considered positive when at least 50% of tumor cells expressed bcl-2 protein. There were 193 (66%) bcl-2+ patients and 99 (34%) bcl-2- patients. The response rates for R-CHOP and CHOP were, respectively, 78% and 60% (P =.01) in bcl-2+ patients and 76% and 73% (P =.7) in bcl-2- patients. At a median of 2 years of follow-up, R-CHOP was significantly associated with a better overall survival than CHOP in bcl-2+ patients (67% +/- 9% versus 48% +/- 11%, P =.004). In bcl-2- patients there was no statistically significant difference (72% +/- 12% versus 67% +/- 14%, P =.6). In addition, R-CHOP was associated with significantly better event-free survival than CHOP in bcl-2+ patients (58% +/- 10% versus 32% +/- 10%, P <.001) but not in bcl-2- patients (60% +/- 13% versus 40% +/- 15%, P =.13). Multivariate analysis confirmed the significant benefit for survival and event-free survival of R-CHOP in bcl-2+ patients. These results suggest that rituximab is able to prevent chemotherapy failure in patients with bcl-2 protein overexpression.