The observation that approximately 70% of HIV-infected pregnant women do not transmit infection vertically suggests that antibody therapy may be effective in the prevention of transmission of HIV infection from mother to child. Currently, there is an incomplete understanding of the processes involved in vertical transmission of HIV infection. The elucidation of the serological basis of maternal immunity as it relates to protection from vertical transmission is the goal of this study. We have screened 20 maternal sera from HIV+ individuals of known vertical transmission status for reactivity with 31 peptides spanning the entire envelope glycoprotein of HIV-1. Of interest was reactivity to regions outside of the V3 loop of gp120. The findings have been examined in relationship to transmission status, as well as to in vitro anti-HIV-1 biological activity. Our results indicate that lack of vertical transmission is correlated with high viral neutralization activity, but not with antisyncytial activity nor with binding to the V3 peptides examined in this study. Also, the transmission group bound to fewer gp41 peptides when compared with the nontransmission group, suggesting that immune responses to gp41 may be important in preventing transmission. These findings may provide insights into the design of passive immunotherapies.