RANTES (regulated on activation normal T cell expressed and secreted), a ligand for the CC chemokine receptor 5, potently inhibits HIV-1 replication in vitro. We tested the influence of four RANTES single nucleotide polymorphism (SNP) variants and their haplotypes on HIV-1 infection and AIDS progression in five AIDS cohorts. Three SNPs in the RANTES gene region on chromosome 17 (403A in the promoter, In1.1C in the first intron, and 3′222C in the 3′ untranslated region) are associated with increased frequency of HIV-1 infection. The common In1.1C SNP allele is nested within an intronic regulatory sequence element that exhibits differential allele binding to nuclear proteins and a down-regulation of gene transcription. The In1.1C allele or haplotypes that include In1.1C display a strong dominant association with rapid progression to AIDS among HIV-1-infected individuals in African-American, European-American, and combined cohorts. The principal RANTES SNP genetic influence on AIDS progression derives from the down-regulating RANTES In1.1C allele, although linkage disequilibrium with adjoining RANTES SNPs including a weaker up-regulating RANTES promoter allele (−28G), can modify the observed epidemiological patterns. The In1.1C-bearing genotypes account for 37% of the attributable risk for rapid progression among African Americans and may also be an important influence on AIDS progression in Africa. The diminished transcription of RANTES afforded by the In1.1C regulatory allele is consistent with increased HIV-1 spread in vivo, leading to accelerated progression to AIDS.