The high affinity Fcγ receptor, FcγRI, is unique among the three classes of macrophage Fcγ receptors not only in its affinity for IgG, but also in the structure of its cytoplasmic domain. FcγRIIA and the γ subunit of FcγRIIIA have tyrosinecontaining motifs within their cytoplasmic domains that are phosphorylated when crosslinked and that are required for phagocytosis by COS-I cell transfectants. In contrast to these other Fcγ receptors, FcγRI does not contain cytoplasmic tyrosines and does not induce phagocytosis in COS-1 transfectants. We transfected wild-type (WT) and mutant (MT) FcγRI lacking the cytoplasmic domain into COS-1 cells and murine macrophages and assessed phagocytosis using IgG-coated red blood cells (RBCs) and RBCs-conjugated with Fab anti-human FcγRI monoclonal antibody (mAb). FcγRI, in contrast to FcγRIIA, did not induce phagocytosis in COS cells. However, both WT and MT FcγRI induced phagocytosis in murine macrophages, and phagocytosis was inhibited by the tyrosine kinase inhibitor tyrphostin 23. Human monocytes also phagocytosed FcγRI-targeted RBCs, and activation of FcγRI on monocytes with Fab anti-FcγRI induced phosphorylation of FcγRI on tyrosine residues. However, FcγRI activation of FcγRI-FcγRIIA COS-1 cotransfectants did not induce tyrosine phosphorylation of FcγRIIA, and coexpression of FcγRI and FcγRIIA in COS cells did not confer FcγRI phagocytic capability. In contrast, coexpression in COS-1 cells of FcγRI with the γ subunit of FcγRIIIA conferred phagocytic function to both FcγRI and the MT FcγRI lacking the cytoplasmic domain. Thus, FcγRI does not require its cytoplasmic domain to mediate a phagocytic signal and interacts with the γ subunit of FcγRIIIA to induce phagocytosis.