Passive immunization with synergistic combinations of human monoclonal antibodies (mAbs) directed against conserved epitopes of the human immunodeficiency virus (HIV) envelope completely protected 13 out of 16 rhesus monkeys challenged intravenously or orally with chimeric simian-human immunodeficiency virus (SHIV) strains; partial protection was seen in another two. A high degree of protection was seen among orally challenged neonates. Thus, we propose that passive immunization with synergistic combinations of neutralizing human mAbs may be effective in preventing maternal HIV transmission when given as post-exposure prophylaxis at birth and as prophylaxis against milk-borne transmission. Because we only used mAbs with well-defined epitope specificities, our studies also yield key information for designing AIDS vaccines: the correlates of immune protection. Vaccine strategies that can evoke antibody responses to epitopes recognized by the mAbs used in our primate studies could be important components of successful AIDS vaccines.