The Killer Ig-like receptors (KIRs) on NK cells regulate NK activity via the recognition of specific HLA class I products on the surface of target cells. To investigate the level at which these genetically polymorphic receptors and ligands influence HIV-1 disease progression, we examined the effect of KIR and HLA genotype on HIV outcome. We observed a significant association between particular combinations of KIR epitopes expressed by HLA-B/-C haplotypes and propose that the repertoire of KIR epitopes expressed by HLA-B and HLA-C alleles within the context of particular haplotypes may be an important component of the NK mediated immune response to HIV and/or other infectious pathogens.