Mutant alleles of the chemokine receptors CCR5 and CCR2 affect the susceptibility to HIV infection as well as the rate of disease progression. In this article the authors report the results of a survey for presence of the common Delta32ccr5 and ccr2b-V64I mutant alleles in 472 individuals of a multiethnic cohort. Hispanic Americans had the highest observed frequency of the Delta32ccr5 allele (3.57%), whereas African Americans had a lower frequency (1.55%). The mutant allele was absent in Asian Americans and Native Americans. Thus, the Delta32ccr5 allele segregates in populations with a significant white admixture and is rare in genetically distant non-European groups. Native Americans had the highest occurrence of the ccr2b-V64I allele (31.13%), whereas African Americans, Asian Americans, and Hispanic Americans had much lower frequencies (14.36%, 11.94%, and 14.37% respectively). This mutation is probably an ancient one, occurring before the migration of the ancestors of Native Americans across the Bering Straits to the Americas. The twofold greater frequency of ccr2b-V64I in modern Native Americans probably reflects a founder effect. The observed population differences in Delta32ccr5 and ccr2b-V64I frequencies, considered together with their documented effects on sensitivity to HIV infection and rate of disease progression, have implications for HIV transmission patterns in the United States, as well as for AIDS prediction, monitoring, and treatment.