The FUT2 gene encodes the enzyme alpha (1,2) fucosyltransferase, which determines expression of blood-group antigens on mucosal epithelial cell surfaces and in secretions. Homozygotes for a specific stop mutation in FUT2 (nonsecretors) cannot produce this enzyme and thus are unable to express blood group antigens. Nonsecretor status is associated with a decreased risk of several respiratory viral infections. By use of molecular genotyping, 2 populations of Senegalese women were examined for polymorphisms of the FUT2 gene. Among Senegalese commercial sex workers, absence of FUT2 (nonsecretor genotype) was associated with reduced risk of human immunodeficiency virus (HIV) type 1 infection (odds ratio [OR] adjusted for cervical and vaginal infection, 0.18; 95% confidence interval [CI], 0.04-0.90) and HIV-2 infection (adjusted OR, 0.43; 95% CI, 0.13-1.39), although the latter was not statistically significant. Modification of cell surface carbohydrates at mucosal surfaces determined by the FUT2 gene may underlie the protective association against heterosexual HIV infection.