An effective AIDS vaccine must protect against sexual transmission of human immunodeficiency virus (HIV). We have developed a model of sexually transmitted AIDS using vaginal infection of female rhesus macaques with simian immunodeficiency virus (SIV) for studies of pathogenesis and evaluation of vaccines. We previously showed that direct inoculation of the vaginal submucosa (perivaginal inoculation) with a live-attenuated SIV, SIVmac1A11, induces immune responses that are similar in quality to those of virulent virus. Such immune responses may reduce virus load, but may not be of sufficient strength or duration to prevent infection by virulent virus inoculated intravaginally. We also recently found that SIV-specific CTL precursors could be re-stimulated after replication of SIVmac1A11 wanes, by administering a second perivaginal inoculation consisting of either live-attenuated SIV or whole inactivated SIV without any adjuvant. After intravaginal challenge with pathogenic SIVmac251, five of six perivaginally immunized macaques had 10-1,000 fold lower infectious virus levels in peripheral blood mononuclear cells and 10 to 10,000 fold lower viral RNA (measured by the Chiron branched chain DNA assay) levels in plasma than naive control macaques. Because women are often exposed to relatively low doses of HIV by sexual contact, a vaccine that could generate genital immune responses that significantly reduced levels of virus transmitted during vaginal exposure might prevent or delay systemic infection. *KEY* HIV vaccine, Sexual transmission, AIDS, Live-attenuated SIV, Vaginal immunization