Background:The majority of infants infected through maternal transmission acquire the virus during birth or postpartum through breastfeeding: mucosal exposure is considered to be a major route of infection.Objectives:To develop passive immunization with human neutralizing monoclonal antibodies (mAbs) against mother-to-child transmission of HIV during delivery and through breastfeeding.Design:An oral challenge model in newborn rhesus macaques mimicked peri- and postpartum virus transmission.Methods:Neonatal rhesus macaques were challenged orally with the highly pathogenic, chimeric simian–human immunodeficiency virus SHIV89.6P and given post-exposure prophylaxis with a quadruple combination of neutralizing human mAbs, IgG1b12, 2G12, 2F5, and 4E10, directed against conserved epitopes of HIV envelope glycoproteins. Control animals were virus challenged but left untreated. All infants were followed prospectively for signs of viremia and immunodeficiency.Results:Two out of four macaque infants treated with neutralizing mAbs showed no evidence of infection; the other two maintained normal CD4 T cell counts. In contrast, all control animals became highly viremic and had profound CD4 T cell losses; three out of four died from AIDS within 1.5–6 weeks of the challenge.Conclusions:Passive immunization with this quadruple neutralizing mAbs combination may represent a promising approach to prevent peri- and postnatal HIV transmission. Furthermore, the epitopes recognized by the four neutralizing mAbs are key determinants to achieve complete protection and represent important targets against which to develop active, antibody-response-based AIDS vaccines.