Molecular mechanisms by which the Src homology 2 domain-containing inositol 5-phosphatase (SHIP) negatively regulates phagocytosis in macrophages are unclear. We addressed the issue using bone marrow–derived macrophages from FcγR- or SHIP-deficient mice. Phagocytic activities of macrophages from FcγRII(b)^−/− and SHIP^−/− mice were enhanced to a similar extent, relative to those from wild type. However, calcium influx was only marginally affected in FcγRII(b)^−/−, but greatly enhanced in SHIP^−/− macrophages. Furthermore, SHIP was phosphorylated on tyrosine residues upon FcγR aggregation even in macrophages from FcγRII(b)^−/− mice or upon clustering of a chimeric receptor containing CD8 and the immunoreceptor tyrosine-based activation motif (ITAM)–bearing γ-chain or human-restricted FcγRIIa. These findings indicate that, unlike B cells, SHIP is efficiently phosphorylated in the absence of an immunoreceptor tyrosine-based inhibition motif (ITIM)–bearing receptor. We further demonstrate that SHIP directly bound to phosphorylated peptides derived from FcγRIIa with a high affinity, comparable to that of FcγRII(b). Lastly, FcγRIIa-mediated phagocytosis was significantly enhanced in THP-1 cells overexpressing dominant-negative form of SHIP in the absence of FcγRII(b). These results indicate that SHIP negatively regulates FcγR-mediated phagocytosis through all ITAM-containing IgG receptors using a molecular mechanism distinct from that in B cells.