Inhibitory killer cell Ig-like receptors (KIR) signal by recruitment of the tyrosine phosphatase Src homology region 2 domain-containing phosphatase-1 to ITIM. In the present study, we show that, surprisingly, KIR lacking ITIM are able to signal and inhibit in the human NK cell line NK92, but not in mouse NK cells. Signaling by mutant KIR is weaker than the wild-type receptor, does not require the transmembrane or cytoplasmic tail of KIR, and is blocked by overexpression of a catalytically inactive Src homology region 2 domain-containing phosphatase-1 molecule. We also demonstrate that mutant KIR signaling is blocked by Abs, which disrupt the interaction between KIR and human leukocyte Ag-C or Abs, which block the interaction between Ig-like transcript 2 (ILT2) and the α3 domain of HLA class I molecules. Thus, although ILT2 expressed in NK92 is insufficient to signal in response to human leukocyte Ag-C alone, ILT2 can signal in a KIR-dependent manner revealing functional cooperation between receptors encoded by two distinct inhibitory receptor families.