The regulation of the innate and the adaptive immune responses are extensively intertwined and tightly regulated. Ag-driven immune responses that are modulated by immune complexes (ICs) are known to inhibit IFN-γ–dependent MHC class II expression. We have previously demonstrated that ICs dramatically inhibit IFN-γ–induced activation of human monocytes through the activation of the FcγRI signaling pathway. In the present study we further explore the mechanisms by which ICs regulate IFN-γ activation of human monocytes. We demonstrate that members of the SRC kinase family (SKF) are key mediators of IFN-γ pathway suppression: inhibitors of the SKF reverse the ability of ICs to suppress IFN-γ signaling. Small interfering RNA was used to target specific members of the SKF. The data indicate that SRC and LYN are both required for ICs to elicit their immunosuppressive activity, whereas FYN does not appear to contribute to this function. Similarly, the kinase SYK, though not a member of the SKF, is also demonstrated to be involved in this IC-mediated immunosuppression. Our data suggest a mechanism whereby ICs directly inhibit inflammatory signals by crosslinking FcγRI, resulting in the activation of the specific phosphotyrosine kinases SRC, LYN, and SYK and the concomitant suppression of the IFN-γ signaling pathway.