Mouse gp49B is an immunoreceptor tyrosine-based inhibitory motif-bearing receptor identified on mast cells and NK cells. In this report, however, we show that this receptor is expressed on macrophages accumulating in the uterine metrial gland in midgestation, along with gp49A that has a very homologous extracellular domain with gp49B but has a short cytoplasmic domain without ITIM. Culture of bone marrow cells in the conditioned medium of the metrial gland resulted in the selective proliferation of macrophages expressing both Fcγ-activating receptors and gp49B inhibitory receptor. Stimulation of macrophages with immobilized IgG, but not with anti-FcγRII/III, induced a considerable amount of TNF-α and IL-10 production, suggesting that the high-affinity receptor for IgG (FcγRI) can transmit activating signals in cytokine production of macrophages. Furthermore, coligation of gp49B with FcγRI resulted in the inhibition of TNF-α production. Thus, our data provide evidence that gp49B is an endogenous negative regulator of macrophage activation and may regulate the function of macrophages during pregnancy.