question: Recombinant vesicular stomatitis virus (VSV) is widely used as a vaccine platform. However, the capacity of VSV-based vaccines to induce mucosal immunity has not been fully investigated. In the present study, a recombinant VSV expressing coxsackievirus B3 (CVB3) major immunogen VP1 has been generated and the immune protection elicited by VSV-VP1 was evaluated. We demonstrated that intranasal delivery of VSV-VP1 can induce a potent antigen-specific mucosal immune response as well as a systemic immune response, particularly the induction of polyfunctional T cells. Importantly, mice immunized with VSV-VP1 were better protected against CVB3-induced viral myocarditis than those receiving a chitosan-formulated DNA vaccine. Increased dendritic cell (DC) maturation in the mesenteric lymph node (MLN) was observed in the mice vaccinated with VSV-VP1, which could be a potential mechanism for the protective immune response. These findings support VSV as a viral delivery vector that can induce robust mucosal immunity that should be considered for further vaccine development.