Intravenous immune globulin (IVIG) suppresses autoantibody-mediated inflammation by inducing and activating the inhibitory Fc receptor FcγRIIb and downstream negative signaling pathways. We investigated the effects of IVIG on cellular responses to interferon-γ (IFN-γ), a potent macrophage activator that exacerbates inflammation. Our study showed that IVIG blocked IFN-γ signaling and IFN-γ-induced gene expression and suppressed IFN-γ function in vivo during immune responses to Listeria monocytogenes and in an IFN-γ-enhanced model of immune thrombocytopenic purpura. The mechanism of inhibition of IFN-γ signaling was suppression of expression of the IFNGR2 subunit of the IFN-γ receptor. The inhibitory effect of IVIG was mediated at least in part by soluble immune complexes and was dependent on FcγRIII but independent of FcγRIIb. These results reveal an unexpected inhibitory role for the activating FcγRIII in mediating suppression of IFN-γ signaling and suggest that inhibition of macrophage responses to IFN-γ contributes to the anti-inflammatory properties of IVIG.