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Recently, attention has been focused on the role of killer cell immunoglobulin-like receptor (KIR)-ligand incompatibility between donor and recipient in allogeneic hematopoietic stem-cell transplantation (ASCT). Although KIR-ligand mismatch is clearly associated with improved survival in haploidentical ASCT for acute myeloid leukemia, its role in unrelated human leukocyte antigen-mismatched ASCT is more controversial. Here we present a retrospective analysis of KIR-ligand–matched (n=167) and mismatched (n=23) unrelated ASCTs for hematologic malignancies performed at a single center. We observed that KIR-ligand mismatch was associated with increased transplantation-related mortality (P=0.02), leading to decreased overall survival (P=0.01). The increased transplantation-related mortality was a consequence of a higher rate of infections (P=0.01), whereas incidence of graft-versus-host disease and leukemic relapse did not differ significantly between the two groups. These results suggest that the presence of donor-derived, alloreactive natural killer cells may interfere with immunity to infection in the early posttransplantation period.