H IV-1 gp120 is an immunoglobulin superantigen which can bind to preimmune serum Ig. We hypothesize that levels of such preimmune antibodies vary in the population and might affect host resistance or susceptibility to viral transmission. This study tests two predictions: (a) levels of preimmune anti-gpl20 Igs are a polymorphic trait; and, (b) these levels are correlated with resistance or susceptibility to HIV-1 transmission. The first prediction was confirmed in a longitudinal study of a low-risk seronegative population. In this group, levels of both endogenous anti-gpl20 IgM and IgG varied widely, but were characteristic and stable for each individual. The second prediction was addressed in a study of participants of the Multicenter AIDS Cohort Study, in which men "susceptible" and "resistant" to HIV infection were identified based on numbers of sexual partners and eventual seroconversion. Specimens consisted of archival sera obtained > 2 yr before seroconversion. Men in the susceptible population (low-risk seroconverters) were distinguished by low levels of anti-gpl20 IgG. We conclude that the level of preimmune anti-gpl20 IgG is a polymorphic population trait, and low levels are a potentially specific and significant factor in homosexual transmission of HIV infection.