A vaccine against AIDS will probably have to protect against challenge both by viable virus-infected cells and by cell-free virus. Eight cynomolgus macaques infected with attenuated simian immunodeficiency virus (SIV) were challenged (four each) with cell-free and cell-associated SIV. All were protected, whereas eight control were all infected after challenge. These findings show that live- attenuated vaccine can onfer protection against SIV in macaques. Extrapolation to human beings will require extensive evaluation of the safety of attenuated retroviruses. Alternatively, the mechanism of this potent protection must be understood and reproduced by less hazardous means.