In a population-based case-control study, 182 human immunodeficiency virus (HIV)—positive persons and 135 healthy control subjects were enrolled from the metropolitan area of Medellin, Colombia. Four genotypes of the natural resistance—associated macrophage protein l (NRAMP1) gene (5′ GT repeat, 274C/T, 469+14G/T, and 823C/T) were associated with altered risk of HIV infection (P = .015, .020, and .035, respectively). Three of these markers (5′ [GT]n, 274C/T, 469+14G/T) are in strong linkage disequilibrium, and genotypes of these markers are associated with reduced risk of HIV infection with relative risks (RRs) of 0.35 (95% confidence interval [CI], 0.14–0.91), 0.31 (CI, 0.10–0.93), and 0.24 (CI, 0.08–0.72), respectively. Conversely, heterozygosity at the fourth independent marker (823C/T) was associated with increased risk of HIV infection (RR, 2.29; CI, 1.06–4.92). These findings suggest that NRAMP1 modifies risk of HIV infection.