DARC is a receptor for CC and CXC chemokines, which is expressed on red blood cells (RBC) and some endothelia. It also serves as a receptor on RBC for Plasmodium vivax. We have found that DARC can specifically bind HIV-1 and mediate efficient transfer of HIV-1 to target cells. This interaction can be abrogated by the presence of DARC specific ligands and antibodies. Surprisingly, the same panel of HIV-1 isolates was unable to use DARC as a functional co-receptor however, several HIV-2 isolates can utilise DARC in conjunction with CD4 to gain entry into cells. Most Africans do not express DARC on RBC owing to a mutation in the DARC promoter which prevents binding of the erythroid-specific transcription factor, GATA-1. Another common human polymorphism alters an amino acid in the N-terminal extracellular domain of DARC. Using a cohort of >3400 Americans of African (AA) and European (EA) descent, we have found that both these DARC single nucleotide polymorphisms (SNPs) affect HIV/AIDS. AA individuals who are homozygous for the mutant promoter SNP, -46C/C, have a 150% higher risk of acquiring HIV (p=0.001) but have slower disease progression once infected (p=0.01). This beneficial effect on disease progression observed in AA is equivalent to that seen in EA heterozygous for the ∆32 deletion in CCR5. Regarding the coding region SNP, individuals homozygous for the FyB, ancestral allele, had a greater risk of infection (p>0.001), followed by slower disease progression (p=0.001) than individuals who were heterozygous or homozygous for the FyA allele. These differences in the risk of acquiring HIV-1 infection could go some way to explaining the higher prevalence of the virus in Africa.