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While gastric adenocarcinoma is the most serious consequence of Helicobacter pylori infection, not all infected persons develop this pathology. Individuals most at risk of this cancer are those in whom the bacteria colonize the acid-secreting region of the stomach and subsequently develop severe inflammation in the gastric corpus. It has been reported anecdotally that male mice become infected with greater numbers of H. pylori bacteria than female mice. While investigating this phenomenon, we found that increased H. pylori infection densities in male mice were not related to antibody production, and this phenomenon was not normalized by gonadectomy. However, the gastric pH in male 129/Sv mice was significantly elevated compared with that in female mice. Differences in colonization were evident within 1 day postinfection and significantly arose due to colonization of the gastric corpus region in male mice. This provided a potential model for comparing the effect of corpus colonization on the development of gastritis. This was explored using two models of H. pylori-induced inflammation, namely, 2-month infections of Muc1 ؊/؊ mice and 6-month infections of wild-type 129/Sv mice. While H. pylori infection of female mice induced a severe, corpus-predominant atrophic gastritis, to our surprise, male mice developed minimal inflammation despite being colonized with significantly more H. pylori bacteria than female controls. Thus, colonization of the gastric corpus in male mice was associated with a loss of inflammation in that region. The suppression of inflammation concomitant with infection of the gastric corpus in male mice demonstrates a powerful localized suppression of inflammation induced at sites of H. pylori colonization.The pathological consequences of chronic infection by the gastric pathogen Helicobacter pylori include peptic ulcer disease and gastric adenocarcinoma, which globally is the second leading cause of death due to malignancy (20,35). The key features believed to dictate whether an infected individual will develop these diseases are the severity and the localization of the inflammation that results from this infection. Individuals who develop antrum-predominant gastritis, while at risk of duodenal ulcers, appear protected from gastric cancer. In contrast, severe gastritis in the stomach corpus and low gastric acid production (hypochlorhydria) are major risk factors for gastric cancer. Any factor that facilitates H. pylori colonization of the gastric corpus and/or reduces gastric acid secretion may therefore contribute to host susceptibility to gastric cancer. For example, gastric pH can influence the gastric localization of H. pylori colonization within the stomach (13), and polymorphisms believed to increase production of the proinflammatory cytokine interleukin 1␤ (IL-1␤), which is known to have potent acid-suppressive activity, are associated with an increased risk of gastric cancer in Caucasians (8).Another host factor that appears to play an important role in regulating the inflammatory respon...