OBJECTIVE: To evaluate the correlation between seroreactivity to peptides corresponding to the V3 loop of the major envelope glycoprotein from different HIV-1 strains and the risk of heterosexual HIV-1 transmission. METHODS: Sera from 39 infected individuals (16 transmitters and 23 non-transmitters) were tested for reactivity against synthetic peptides representing sequences of the V3 loop apex from HIV-1 strains MN, SC, WMJ2, RF and IIIB. RESULTS: A skewed distribution in seroreactivity to RF and IIIB peptides was observed between the two groups: reactivity was more prevalent in sera from non-transmitting than from transmitting individuals. Reactivity to the MN, SC and WMJ2 peptides was very frequent and there were no differences between the two groups. CONCLUSION: These data suggest that antibodies reactive with a larger set of V3 apex peptides (i.e., cross-reactive antibodies) could play a role in the prevention of heterosexual transmission.