Most viral vaccines currently in use in humans are live attenuated strains of virus that lack pathogenic potential. In general, such live attenuated vaccines induce the strongest longest-lasting immunity. Live attenuated strains of human immunodeficiency virus type 1 (HIV-1) have not been previously considered as vaccines for acquired immunodeficiency syndrome (AIDS) because of an inability to envision how their safety could be adequately assured. This report describes a means for making live, nonpathogenic strains of SIV_mac and HIV-1 that cannot revert to a virulent form and a stepwise scheme for demonstrating their safety. Replication-competent, multiply deleted derivatives that are currently being tested are missing combinations of auxiliary genes (nef, vpr, vif, vpx, vpu) and certain control elements in the negative regulatory element (NRE) of the long terminal repeat (LTR). Since these genomic regions are in large part conserved among the SIVs and HIVs, they are likely to be important for the virus life cycle in vivo. Consistent with this line of reasoning, a replication-competent nef deletion mutant of SIV_mac apparently has lost most or all of its pathogenic potential, yet it still induces strong immune responses. Multiply deleted derivatives of SIV_mac and HIV-1 will have to be extensively tested in animal models prior to moving a promising HIV-1 candidate to initial trials in high-risk human volunteers. Definitive evidence for safety and general acceptance for this approach can only evolve gradually over a prolonged period of time.