The critical role of chemokine receptors (CCR5 and CXCR4) in human immunodeficiency virus–type 1 (HIV-1) infection and pathogenesis prompted a search for polymorphisms in other chemokine receptor genes that mediate HIV-1 disease progression. A mutation (CCR2-64I) within the first transmembrane region of theCCR2 chemokine and HIV-1 receptor gene is described that occurred at an allele frequency of 10 to 15 percent among Caucasians and African Americans. Genetic association analysis of five acquired immunodeficiency syndrome (AIDS) cohorts (3003 patients) revealed that although CCR2-64I exerts no influence on the incidence of HIV-1 infection, HIV-1–infected individuals carrying theCCR2-64I allele progressed to AIDS 2 to 4 years later than individuals homozygous for the common allele. BecauseCCR2-64I occurs invariably on a CCR5-+–bearing chromosomal haplotype, the independent effects ofCCR5-Δ32 (which also delays AIDS onset) andCCR2-64I were determined. An estimated 38 to 45 percent of AIDS patients whose disease progresses rapidly (less than 3 years until onset of AIDS symptoms after HIV-1 exposure) can be attributed to theirCCR2-+/+ or CCR5-+/+ genotype, whereas the survival of 28 to 29 percent of long-term survivors, who avoid AIDS for 16 years or more, can be explained by a mutant genotype forCCR2 or CCR5.