In approximately 5% to 10% of gastric mucosa-associated lymphoid tissue (MALT) lymphomas, evidence of Helicobacter pylori infection is absent, and their pathogenesis is poorly understood. We reviewed the clinical data and histology, and we examined t(11;18)(q21;q21) and BCL10 expression pattern in 17 such cases. In each case, the absence of H pylori was confirmed by negative serology and histology/immunohistochemistry. Five cases with stage I(E) disease were first treated with antibiotics, and none of them showed any endoscopic or histologic response. Review of the histology failed to identify any apparent difference between gastric MALT lymphomas with and without H pylori infection. Reverse transcription-polymerase chain reaction (RT-PCR) showed t(11;18)(q21;q21) in 9 (53%) of 17 cases, more frequent in lymphomas at stage II(E) or above (5 of 6) than those at stage I(E) (3 of 10). Two t(11;18)(q21;q21)-positive lymphomas were treated by partial gastrectomy and more than 16 years later showed lymphoma relapse in the gastric stump with dissemination to other mucosal sites, poorly responsive to therapy. BCL10 nuclear expression was observed in 7 of 8 t(11;18)(q21;q21)-positive cases and 4 of 7 t(11;18)(q21;q21)-negative cases, including one case suspicious for a BCL10-involved chromosomal translocation. Our results show that t(11;18)(q21;q21) occurs at a high frequency in H pylori-negative gastric MALT lymphomas. Translocation-positive gastric MALT lymphomas tend to be aggressive, and patients with such lymphomas might benefit from prompt treatment and close follow-up.