HLA allele mismatches will provoke T-cell alloreactivity after allogeneic stem cell transplantation. As donors and recipients are usually HLA matched, the public HLA epitopes that are recognized by natural killer (NK) cells (NK epitopes) are rarely mismatched, and therefore there is rarely potential for NK alloreactivity arising from the absence of ligands for inhibitory killer immunoglobulin-like receptors (KIR). Transplants using related donors sharing only one haplotype (haploidentical donors) represent a setting in which NK epitopes are often mismatched, thus resulting in the potential for NK alloreactivity. We have analyzed engraftment, acute graft vs host disease (GVHD), leukemia relapse, and survival in 62 haploidentical transplants in relationship with potential NK alloreactivity, inhibitory, and activating KIR genes of class I HLA NK epitopes. Potential NK alloreactivity in the rejection direction was not associated with any outcome variable. Potential NK alloreactivity in the GVHD direction was associated with an increased incidence of severe GVHD and poorer patient survival but not with non-engraftment nor leukemia relapse. A higher number of activating KIR receptors in the genome of the donor was associated with a higher prevalence of GVHD. These results suggest that lack of extensive T-cell depletion in haploidentical transplantation is associated with high GVHD rates and diminishes the benefits of NK-cell alloreactivity.