We have identified two novel human cDNA encoding transmembrane proteins of the immunoglobulin superfamily (IgSF). The two cDNA, called immunoglobulin-like transcripts 1 and 2 (ILT1 and ILT2), are expressed in myeloid and lymphoid cells and are homologous to bovine Fc gamma2R, human killer cell inhibitory receptors (KIR), human Fc alphaR, and mouse gp49. Furthermore, ILT1 and ILT2 are encoded on chromosome 19, as are Fc alphaR and KIR. While the ILT1 and ILT2 extracellular domains are homologous, the transmembrane and cytoplasmic domains differ substantially. ILT1 has an arginine within the transmembrane region, followed by a short cytoplasmic tail, similar to human Fc alphaRI and bovine Fc gamma2R. ILT2 has a long cytoplasmic tail, which contains two YxxV and two YxxL pairs similar to the immunoreceptor tyrosine-based inhibitory motifs in KIR that are known to bind the phosphotyrosine phosphatase SHP-1. These cytoplasmic features suggest that ILT1 and ILT2 may mediate novel transmembrane signals by which myeloid and lymphoid cell responses can be either activated or inhibited.