Zona pellucida 3 (ZP3) acts as the primary sperm receptor, induces autoantibody that can prevent oocyte fertilization and has been proposed as a vaccine candidate for contraception in humans. Due to the elicited autoreactive T cell inflammation that causes ovarian destruction, ZP3-based vaccine with removed T epitopes from the ZP3 is considered as a preferred approach. We present here a new strategy to eliminate the T cell inflammation while retaining a high level of antibody by co-immunization of mZP3 DNA and protein vaccines, which resulted in a higher reduction rate of fertility in this group. Histological analysis showed that there were normal follicular developments of infertile mice in the co-immunized group; while other vaccine groups of the most infertile mice lacked mature follicles. There was a significant correlation between normal follicular development and the inhibition of T cell response in co-immunized mice. At the same time, co-immunization reduced the production of inflammatory cytokine, IFN-γ, and increased the productions of IL-10 and FoxP3 in CD4 T cells, suggesting the anti-inflammation may be via a T regulatory function. The results indicate that co-immunization of mZP3 DNA- and protein-based vaccines can reduce fertility without interfering with the normal follicular development and present a novel strategy to develop a contraceptive vaccine in humans. Copyright © 2007 John Wiley & Sons, Ltd.