Despite the proven ability of immunization to reduce Helicobacter infection in mouse models, the precise mechanism of protection has remained elusive. In this study, we evaluated the role of IL-22 in the vaccine-induced reduction of Helicobacter infection. We first observed that IL-22 production is increased in the stomach during the vaccine-induced reduction of Helicobacter infection. These high IL-22 levels were associated with an increase production of antimicrobial peptides (AMP) such as RegIIIβ by stomach epithelial cells. FACS analysis revealed that the main source of IL-22 is CD4+ T cells especially IL-17 producing cells. In immunized mice, intraperitoneal injection of anti-IL-22 antibodies significantly impaired the vaccine-induced reduction of Helicobacter infection. Importantly, IL22-Fc injections to mice chronically infected with Helicobacter dramatically reduced bacterial load. Finally cationic AMP (AMPc) were extracted from stomachs and incubated with Helicobacter to evaluate their bactericidal effects. AMPc extracted from stomachs of vaccinated mice or mice injected with IL-22Fc kill Helicobacter in vitro. On the contrary, AMPc extracted from stomachs of non-immunized or immunized mice injected with anti-IL-22 antibodies did not kill Helicobacter. Collectively theses results demonstrated that IL-22 plays a critical role in vaccine-induced reduction of Helicobacter infection, by inducing the expression of AMPc capable to kill Helicobacter.