Recombinant (r) fertilization antigen (FA)-1 was investigated for its immunocontraceptive effect using the mouse as a model. Active immunization with the murine rFA-1 antigen raised high antibody titers in all the immunized mice (n = 16 in two trials); these titers were long lasting and reached preimmunization levels by the 255th day. There was a significant (p < 0.0001) effect (64% reduction in trial I and 70% reduction in trial II) in fertility of immunized animals compared to PBS-control animals (n = 22 in two trials). The effect on fertility was reversible. When the antibody titers declined to control levels, all the animals conceived and delivered healthy babies without a significant (p > 0.05) effect on the litter size compared to that of controls. There was a significant (p = 0.025) correlation (r = 0.76) between the reduction in fertility and the circulating rFA-1 antibody titers. Anti-rFA-1 antibodies from immunized mice, and not the immunoglobulins from the PBS-control mice, significantly (p < 0.001) blocked murine sperm binding to zona pellucida and in vitro fertilization of murine oocytes. In a Western blot procedure, the anti-rFA-1 antibodies specifically recognized the protein band of approximately 47 kDa (dimeric form of cognate FA-1 antigen) only in the protein extract of testes and not in the extracts of somatic tissues tested, namely kidney, liver, intestine, spleen, muscle, heart, lung, brain, and ovary. In conclusion, our data indicate that active immunization with rFA-1 antigen induces a strong and sperm/testis-specific antibody response that causes a reversible inhibition of fertility by affecting sperm-zona binding and the fertilization process. These findings suggest that rFA-1 antigen is an exciting candidate for the development of a contraceptive vaccine.