Inactivated plasma collected from either SIV-infected or peptide-vaccinated macaques was transferred into 17 naive rhesus monkeys. Two additional macaques received normal plasma and served as controls. Following transfer all 19 monkeys were inoculated with SIV. While the controls became infected and were virus-isolation-positive, 3 of 6 recipients of SIV peptide vaccine plasma and 9 of 11 recipients of SIV-infected monkey plasma were protected. None of the 12 protected animals became virus-isolation-positive or seroconverted within 100 days of follow-up. One, however was SIV-PCR-positive. All 12 protected animals were rechallenged 100 days after the initial inoculation; 8 became infected and yielded virus as expected, but 4 remained uninfected. One of the latter was the SIV-PCR-positive monkey mentioned above, suggesting that cryptic SIV infection may be of significance in immunological protection. The results demonstrate that envelope anti-peptide antibodies have similar protective potential in vivo as antibodies directed to the whole virus. In vitro neutralization competition assays performed with sera from vaccinated macaques in the presence of the free peptides suggest that of the four conserved envelope peptides of the vaccine, the two originating from gp41 rather than the two from gp120 are responsible for inducing the neutralizing anti-syncytial activity.