FcγRI depends for its biological function on both the intracellular domain of the α-chain and associated Fc receptor (FcR) γ-chains. However, functional protein effectors of FcγRI's intracellular domain have not been identified. In this study, we identified periplakin (PPL) as a selective interacting protein for the intracellular tail of FcγRI but no other activatory FcRs. The interaction was confirmed by coimmunoprecipitation and blot-overlay assays. PPL and FcγRI colocalized at the plasma membrane in monocytes and cell transfectants, and both were up-regulated by IFN-γ. By expressing C-terminal PPL in transfectants, we established a pivotal role for this protein in FcγRI ligand binding, endocytosis, and antigen presentation. These data illustrate that intracellular protein interactions with a multisubunit FcR α-chain can confer unique properties to the receptor.