Natural killer (NK) cells control viral infection in part through the interaction between killer cell immunoglobulin-like receptors (KIRs) and their human leukocyte antigen (HLA) ligands. We investigated 504 anti-retroviral (ART)-free Japanese patients chronically infected with HIV-1 and identified two KIR/HLA combinations, KIR2DL2/HLA-C*12:02 and KIR2DL2/HLA-C*14:03, that impact suppression of HIV-1 replication. KIR2DL2(+) NK cells suppressed viral replication in HLA-C*14:03(+) or HLA-C*12:02(+) cells to a significantly greater extent than did KIR2DL2(-) NK cells in vitro. Functional analysis showed that the binding between HIV-1-derived peptide and HLA-C*14:03 or HLA-C*12:02 influenced KIR2DL2(+) NK cell activity through reduced expression of the peptide-HLA (pHLA) complex on the cell surface (i.e., reduced KIR2DL2 ligand expression), rather than through reduced binding affinity of KIR2DL2 to the respective pHLA complexes. Thus, KIR2DL2/HLA-C*12:02 and KIR2DL2/HLA-C*14:03 compound genotypes have protective effects on control of HIV-1 through a mechanism involving KIR2DL2-mediated NK cell recognition of virusinfected cells, providing additional understanding of NK cells in HIV-1 infection.