Abstract Background We previously reported that H. pylori-positive gastric DLBCL, with or without evidence of MALT origin, may respond to H. pylori eradication therapy. In this study, we further investigated the clinicopathologic features of H. pylori-positive DLBCL without histologic evidence of MALT origin. Methods We reviewed consecutive cases of gastric DLBCL without histologic evidence of MALT origin. H. pylori infection was documented by histologic examination, a urease test or bacterial culture. H. pylori-positive cases were further examined for CagA protein expression. Results A group of 45 patients positive for H. pylori were not histomorphologically different from a group of 48 patients negative for H. pylori. However, patients with H. pylori infection had a better International Prognostic Index score (0-1, 70% vs 30%, P = ·001), a lower clinical stage (I-IIE1, 73% vs 33%, P < [[Unable to Display Character: ∙]]001), a better tumor response to chemotherapy (complete response, 80% vs 50%, P = .01), and significantly better 5-year event-free survival (EFS) (71% vs 24%, P < [[Unable to Display Character: ∙]]001) and overall survival (OS) (73% vs 30%, P < [[Unable to Display Character: ∙]]001). CagA expression, as defined by more than 5% of tumor cells with CagA staining, was identified in 23 (68%) of 34 H. pylori-positive tumors. Compared with the 11 H. pylori-positive but CagA-negative cases, the 23 H. pylori-positive, CagA-positive cases were associated with significantly better 5-year EFS (73% vs 15%, P = [[Unable to Display Character: ∙]]002) and OS (91% vs 27%, P = [[Unable to Display Character: ∙]]001). Conclusion H. pylori-positive gastric DLBCL, particularly with CagA expression in tumor cells, appears to be a distinct tumor entity, sharing some key clinicopathologic features with H. pylori-associated gastric MALT lymphoma. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1747.