We have shown that addition of G-CSF-mobilized peripheral blood progenitor cells to the marrow inoculum allows engrafment of T cell-depleted, haplo-identical marrow transplants for acute leukemia. Here, we report the post-grafting emergence of a large, donor-type CD3 + /CD8 + T cell receptor (TcR)-αβ + cell population, barely detectable in normal subjects, that expresses 58kD, “p58”, inhibitory NK receptors for HLA-C locus alleles. Analysis of >900 clones revealed that 40% to 80% of these T cells exhibit NK-like function, i.e. they lysed class I-negative targets and were functionally blocked by class I alleles on target cells. MAb-mediated blocking of class I recognition by these cells induced lysis of HLA-protected, autologous targets. The class I-mediated inhibitory signaling through the NK receptors also blocked TcR/CD3-triggered cytotoxicity of these cells, indicating that their antigen-specific responses may be impaired. However, the NK-like function of these cells allows them to discriminate normal cells, protected from lysis, from leukemic cells which were lysed and may be targets for a graft-versus-leukemia effect.