Simian AIDS (SAIDS) is an endemic disease of macaques that is etiologically linked to infection by a type D retrovirus. We have cloned a type D retrovirus (SRV-2/WASH) isolated from a macaque with retroperitoneal fibromatosis and SAIDS. A recombinant vaccinia virus (V-senv5) that expresses the envelope glycoprotein of SRV-2/WASH has been constructed and inoculated into macaques. Four V-senv5-immunized animals, together with four controls, were challenged intravenously with one million infectious virus particles of SRV-2/WASH. All four controls seroconverted and became infected. In contrast, none of the V-senv5-immunized animals became infected despite the large challenge dose and were seropositive only against the immunizing env-antigens. We have identified envelope peptides that protect macaques from infection with the simian immunodeficiency virus, SIV/Mne, a primate lentivirus closely related to HIV-2. The immunogen consists of two peptides at the amino- and carboxy-terminal ends of the envelope protein gpl2O and two peptides at the aminoterminal end of the transmembrane protein gp32/gp4l. These peptides were initially chosen because they were immunodominant; 43 to 100% of HIV-1- infected individuals or SIV-infected macaques had antibodies that recognized those epitopes. The four peptide sequences are also highly conserved among the North American and Zairean HIV-1 virus isolates that have been sequenced (86 to 100% amino acid identity). All four peptides were purified ind inoculated into three macaques; two animals generated antibodies that neutralized SIV/Mne infectivity in vitro. These three animals and three controls were challenged intravenously with 100 infectious particles of SIV. All the controls seroconverted and became infected, whereas two of the three vaccinated animals did not become infected. This is the first description of a peptide vaccine that is effective in prevention of SIV infection.