In 1716 individuals--801 human immunodeficiency virus (HIV)-1-seropositive individuals, 217 high-risk HIV-1-seronegative individuals, and 698 general HIV-1-seronegative individuals--from a Seattle cohort and a Multicenter AIDS Cohort Study cohort, the association between HIV-1 susceptibility and repeat-region polymorphisms in the gene for the dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin-related molecule (DC-SIGNR) was investigated; 16 genotypes were found in the DC-SIGNR repeat region. The DC-SIGNR homozygous 7/7 repeat was found to be associated with an increased risk of HIV-1 infection (17.5% in high-risk HIV-1-seronegative individuals vs. 28.5% in HIV-1-seropositive individuals; P=.0015), whereas the DC-SIGNR heterozygous 7/5 repeat tended to be correlated with resistance to HIV-1 infection (35.5% in high-risk HIV-1-seronegative individuals vs. 27.6% in HIV-1-seropositive individuals; P=.0291). These findings suggest that DC-SIGNR polymorphisms may influence susceptibility to HIV-1.