There are important differences in signaling between the Fc receptor for immunoglobulin G (IgG) FcgammaRIIA, which uses the Ig tyrosine-activating motif (ITAM) within its own cytoplasmic domain, and FcgammaRI, which transmits signals by means of an ITAM located within the cytoplasmic domain of its associated gamma-chain. For example, in transfected epithelial cells and COS-1 cells, FcgammaRIIA mediates phagocytosis of IgG-coated red blood cells more efficiently than does FcgammaRI/gamma, and enhancement of phagocytosis by Syk kinase is more pronounced for FcgammaRI/gamma than for FcgammaRIIA. In addition, structure/function studies indicate that the gamma-chain ITAM and the FcgammaRIIA ITAM have different requirements for mediating the phagocytic signal. To study the differences between FcgammaRIIA and FcgammaRI/gamma, we examined the interaction of FcgammaRIIA and the FcgammaRI/gamma chimera FcgammaRI-gamma-gamma (extracellular domain-transmembrane domain-cytoplasmic domain) with Syk kinase and with the Src-related tyrosine kinases (SRTKs) Hck and Lyn in transfected COS-1 cells. Our data indicate that FcgammaRIIA interacts more readily with Syk than does FcgammaRI-gamma-gamma and suggest that one consequence may be the greater phagocytic efficiency of FcgammaRIIA compared with FcgammaRI/gamma. Furthermore, individual SRTKs affect the efficiency of phagocytosis differently for FcgammaRI-gamma-gamma and FcgammaRIIA and also influence the ability of these receptors to interact with Syk kinase. Taken together, the data suggest that differences in signaling by FcgammaRIIA and FcgammaRI-gamma-gamma are related in part to interaction with Syk and Src kinases and that individual SRTKs play different roles in FcgammaR-mediated phagocytosis.