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