Killer cell immunoglobulin-like receptors (KIRs) recognize different groups of Human Leukocyte Antigen (HLA) class I alleles and are expressed by natural killer (NK) cells and some T lymphocytes. NK cell cytotoxicity is triggered by failure to recognize the appropriate HLA class I ligand on target cells. Recently, it has been shown that HLA class I ligand incompatibility in the graft-versus-host (GvH) direction is associated with a better outcome in haploidentical hematopoietic stem cell transplantation (HSCT). Since KIR genotypes are very diverse in the population, we explored whether or not the donor KIR genotype could affect the graft-versus-leukemia (GvL) effect in the related HLA-identical HSCT setting. We determined the KIR and HLA genotypes of 65 HLA-identical patient–donor siblings. We found that the presence of two activating KIRs, 2DS1 and 2DS2, in the donor was significantly associated with a decreased leukemic relapse rate (P= 0.03; OR= 0.18; 95% CI: 0.037–0.88). Moreover, the probability of relapse at 5 years was significantly lower for patients who received a graft from a donor with the 2DS1 (+) 2DS2 (+) genotype than for those who received a transplant from other donors (17 vs 63%, respectively; P= 0.018). In conclusion, this study suggests that a joint effect of these two selected activating KIRs in the donor might confer some protection against leukemic relapse.