The regulatory roles of Th1 and Th2 cells in immune protection against Helicobacter infection are not clearly understood. In this study, we report that a primary H. pylori infection can be established in the absence of IL-12 or IFN-γ. However, IFN-γ, but not IL-12, was involved in the development of gastritis because IFN-γ−/−(GKO) mice exhibited significantly less inflammation as compared with IL-12−/− or wild-type (WT) mice. Both IL-12−/− and GKO mice failed to develop protection following oral immunization with H. pylori lysate and cholera toxin adjuvant. By contrast, Th2-deficient, IL-4−/−, and WT mice were equally well protected. Mucosal immunization in the presence of coadministered rIL-12 in WT mice increased Ag-specific IFN-γ-producing T cells by 5-fold and gave an additional 4-fold reduction in colonizing bacteria, confirming a key role of Th1 cells in protection. Importantly, only protected IL-4−/− and WT mice demonstrated substantial influx of CD4+ T cells in the gastric mucosa. The extent of inflammation in challenged IL-12−/− and GKO mice was much reduced compared with that in WT mice, indicating that IFN-γ/Th1 cells also play a major role in postimmunization gastritis. Of note, postimmunization gastritis in IL-4−/− mice was significantly milder than WT mice, despite a similar level of protection, indicating that immune protection is not directly linked to the degree of gastric inflammation. Only protected mice had T cells that produced high levels of IFN-γ to recall Ag, whereas both protected and unprotected mice produced high levels of IL-13. We conclude that IL-12 and Th1 responses are crucial for H. pylori-specific protective immunity.