NK cells express cell surface receptors for MHC class I proteins (KIR). Engagement of these receptors inhibits NK cell cytotoxic programs. KIR can be expressed on T cells, and their engagement also results in inhibition of effector functions initiated by the CD3/TCR complex. While human KIR genes belong to the Ig gene superfamily, mouse KIR belong to a family of dimeric lectins. Despite these distinct evolutionary origins, we show here that both HLA-Cw3-specific human p58.183 receptors and H-2D d/k-specific mouse Ly49A receptors recruit the same protein tyrosine phosphatases, PTP1C and PTP1D, upon phosphorylation of critical intracytoplasmic tyrosine residues. These results document a common pathway by which diverse KIR can down-regulate NK and T cell activation programs, and further define the sequence of the immunoreceptor tyrosine-based inhibitory motif (ITIM), initially described in FcgammaRIIB1, and expressed in both human and mouse KIR.