BACKGROUND AND AIMS:: Chronic infection with the bacterial pathogen Helicobacter pylori causes gastric disorders ranging from chronic gastritis to gastric adenocarcinoma. Only a subset of infected individuals will develop overt disease; the large majority remains asymptomatic despite lifelong colonization. This study aims to elucidate the differential susceptibility to H. pylori that is found both across and within populations. METHODS:: We have established a C57BL/6 mouse model of H. pylori infection with a strain that is capable of delivering the virulence factor CagA into host cells through the activity of a Cag-pathogenicity island-encoded type IV secretion system. RESULTS:: Mice infected at 5-6 weeks of age with CagA(+)H. pylori rapidly develop gastritis, gastric atrophy, epithelial hyperplasia and metaplasia in a type IV secretion system-dependent manner. In contrast, mice infected during the neonatal period with the same strain are protected from preneoplastic lesions. Their protection results from the development of H. pylori-specific peripheral immunological tolerance, which requires TGF-beta signalling and is mediated by long-lived, inducible regulatory T-cells, and which controls the local CD4(+) T-cell responses that trigger premalignant transformation. Tolerance to H. pylori develops in the neonatal period due to a biased Treg to T-effector cell ratio, and is favoured by prolonged low-dose exposure to antigen. CONCLUSIONS:: Using a novel CagA(+)H. pylori infection model, we report here that the development of tolerance to H. pylori protects from gastric cancer precursor lesions. The age at initial infection may thus account for the differential susceptibility of infected individuals to H. pylori-associated disease manifestations.