Vasoactive intestinal peptide (VIP) has been found to act as a potent anti-inflammatory factor through regulating the production of both anti- and pro-inflammatory mediators and promoting Th2-type responses. In this study, we used Chicken collagen II-induced experimental arthritis (CIA) model in Wistar rats to investigate the potential effects of VIP on rheumatoid arthritis. Our results showed that in vivo treatment of CIA-induced rats with VIP had great protective benefit at both clinical and histological levels. Disease suppression was associated with the inhibition of T cells proliferation, shifting of the immune response toward a Th2-type response and expanded CD4+CD25+ Treg in the periphery, which inhibited autoreactive T cell activation/expansion. In conclusion, the study provides evidence that VIP had great protective effect on CIA through its inhibition actions on pathogenic T cells.