Infection of domestic cats with the feline immunodeficiency virus (FIV) represents an important veterinary health problem and a useful animal model for the development of vaccines against AIDS. Two experimental FIV vaccines have been developed: one consisting of fixed infected cells and the other of inactivated whole virus. Both vaccines elicited strong CTL responses to FIV and high virus neutralizing (VN) antibody titers. Over 90% of vaccinated cats were protected against intraperitoneal infection with 10 cat infectious dose 50% (10 CID50) of either homologous FIVPet or heterologous FIVDix. As a means to evaluate the mechanism of vaccine protection, cats were either passively immunized with serum antibodies or transfused with peripheral blood cells from FIV-vaccinated cats. Cats passively immunized with vaccine sera or purified vaccine antibodies were protected from homologous FIV infection at a challenge doses which infected all control cats (5 and 10 CID50). Such passive protection was not achieved against heterologous FIV challenge. More importantly, cats transfused with washed blood cells from half-matched vaccinated cat were protected from FIV challenge (20 and 50 CID50). As expected, protection was not observed in cats transfused with cells from either unmatched vaccinated or half-matched unvaccinated cats. Further, only peripheral-blood cells from vaccinated cats had FIV-specific CTL responses to both autologous and half-matched target cells. Overall, these findings suggest that both humoral and cellular immunity are required for optimal vaccine protection.