Vasoactive intestinal peptide (VIP) is well characterized as an endogenous anti-inflammatory neuropeptide and has a brand range of biological functions. In this study, we found increased endogenous VIP expression in mice with concanavalin A-induced hepatitis, a widely used experimental model of immune-mediated liver injury. We investigated further the effect of VIP administration on concanavalin A-induced liver injury. Compared with mice pretreated with PBS, mice pretreated with VIP exhibited much lower plasma levels of aminotransferases, less inflammatory infiltration in the liver and hepatocyte apoptosis. Meanwhile, VIP significantly inhibited the release of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in concanavalin A-injected mice, but markedly elevated the production of anti-inflammatory cytokine interleukine-10 (IL-10). Further investigation demonstrated increased intracellular cAMP concentration after VIP administration, and showed that the protective effect of VIP on concanavalin A-induced hepatitis was mediated mainly through VIP receptor 1 (VPAC(1)). These results suggest that VIP is capable of attenuating immune-mediated liver injury in vivo. This effect is associated with its downregulation of critical inflammatory mediators and its upregulation of anti-inflammatory cytokine through VPAC(1), possibly via the cAMP-dependent pathway.