To assess the effect of mutations at the CCR-2 and CCR-5 loci on heterosexual human immunodeficiency virus (HIV) transmission, 144 persons heterosexually exposed to HIV (infected and uninfected [EU]) and 57 HIV-positive index partners were genotyped. A significantly higher frequency of 64I heterozygotes at CCR-2 was observed in HIV-positive than in EU women (P=.02, relative risk=1.6). The allele frequency of 64I in women was 8% in HIV-positive contacts and 1% in EUs (P<.02). At CCR-5, no difference in the frequency of Delta32 was seen between groups, and the CCR-5 genotypes did not differ in accumulated "at-risk" exposure in EUs. Combining the analysis of the Delta32 and 64I mutations in index partners suggested an additive effect on transmission (P=.10). Thus heterozygosity for 64I at CCR-2 acts as a risk factor for HIV infection of women after heterosexual contact but heterozygosity for Delta32 at CCR-5 has no detectable effect.