Natural killer cells (NK cells) represent an important component of innate immunity with the capacity to kill many tumor and virus-infected cells. The discovery of several classes of killer cell inhibitory receptors expressed by NK cells that bind specific MHC class I ligands on target cells provides detailed insight into the regulation of NK cells. Inhibitory receptors deliver negative signals following MHC ligand binding that abrogate cytotoxicity and, thus, determine the specificity of NK effector cell function. Here, we describe a novel subset of human memory CD4(+) T lymphocytes that display an NK-like pattern of regulation. These CD4(+) T cells display non-MHC-restricted cytotoxicity that is governed by HLA-Cw7 mediated inhibition. In NK cells, such specificity is associated with expression of the inhibitory receptor p58.2. In contrast, neither p58.2 nor other known inhibitory receptors were detected on these non-MHC-restricted CD4(+) T cells. This suggests that these cells are regulated by a hitherto unknown inhibitory receptor. The finding that interactions with MHC molecules downregulate the function of these CD4(+) T cells suggests that these non-MHC-restricted T cells may function to detect and eliminate cells with aberrant MHC expression.