Simian immunodeficiency virus (SIV) was used as a model to study the protective efficacy of an immunization regimen currently being evaluated as candidate vaccines against HIV in human subjects. Four Macaca fascicularis were first immunized with recombinant vaccinia virus expressing the envelope glycoprotein gp160 of SIVmne and then boosted with subunit gp160. Both cell-mediated and humoral immune responses against SIV, including neutralizing antibodies, were elicited. The macaques were shown to be protected from a homologous virus infection as determined by serology, lymphocyte cocultivation, polymerase chain reactions and in vivo transmission analyses. Four unimmunized control animals were readily infected. However, viremia in infected control animals could decrease substantially following the initial phase of infection so that persistent infection might not be readily detectable.