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Killer immunoglobulin-like receptors (KIRs) regulate natural killer (NK) cells in a human leukocyte antigen (HLA)–dependent manner. KIR/HLAmismatched hematopoietic stem cell transplants induce alloreactive NK cells, which prevent leukemia relapse. Certain KIR/HLAcombinations protect against HIV-1 infection, but the effect of KIR/HLAmismatches between sexual partners has never been investigated. In this study, we analyzed the effect of allogeneic KIR/HLAcombinations on HIV-1 transmission in a West African population of HIV-1–discordant and concordant couples. HIV-1–discordant couples were characterized by recipient partners with homozygous KIR2DL2, and by a mismatched recipient partner KIR2DL1/HLA-C2with index partner HLA-C1/C1combination expected to allow licensed missing self NK cell killing of index partners' cells. HIV-1–concordant couples on the other hand were characterized by KIR2DL3homozygous recipient partners with HLA-C1/C2bearing index partners, resulting in a matched KIR/HLAcombination expected to inhibit NK cell killing. In vitro cocultures of healthy donor-derived NK cells and HIV-1 patient-derived CD4+T cells confirmed the involvement of these allogeneic KIR/HLAcombinations in NK cell–mediated CD4+T-cell killing. Our data suggest that KIR/HLAincompatibility between sexual partners confers protection against HIV-1 transmission and that this may be due to alloreactive NK cell killing of the HIV-1–infected partner's cells.