Several combinations of genes encoding KIR3DL1 alleles and their HLA‐Bw4 ligands have been linked with favorable outcomes upon exposure to or infection with human immunodeficiency virus (HIV). Some protective KIR3DL1/HLA‐Bw4 combinations confer elevated natural killer (NK) cell functional potential. The K562‐stimulated functionality of NK cells from KIR3DL1*004/HLA‐Bw4 and control genotype carriers was assessed by flow cytometry and found to be higher in KIR3DL1*004/HLA‐Bw4 carriers. However, a comparison of the frequency of this combined genotype among HIV‐exposed uninfected and HIV‐infected subjects revealed no between‐group differences. Thus, despite its ability to license NK cells, KIR3DL1*004/HLA‐Bw4 is not associated with a reduced risk of infection.