In Sub-Saharan Africa most individuals are homozygous for the DARC promoter mutation, -46T>C, abrogating DARC expression on erythrocytes. It was reported that -46C/C is associated with 40% increase in HIV-1 acquisition in a USA population and may account for 11% of HIV-1 burden in Africa. We determined -46T>C genotypes for HIV-1 infected and uninfected African Americans. We found no evidence that the DARC negative phenotype caused by -46C/C affects HIV infection or rates of progression to AIDS in people of African ancestry. The earlier result is likely due to population substructure that led to inflated associations with DARC -46C/C.