The high-affinity receptor for IgG, FcγRI, shares its capacity to bind IgG2a immune complexes (IgG2a-IC) with the low-affinity receptor FcγRIII and complement factors, hampering the definition of its biological role. Moreover, in vivo, FcγRI is occupied by monomeric IgG2a, reducing its accessibility to newly formed IgG2a-IC. By using a variety of FcγR^−/− mice, we demonstrate that in the absence of FcγRI, the IgG2a-IC-induced cellular processes of phagocytosis, cytokine release, cellular cytotoxicity, and antigen presentation are impaired. FcγRI^−/− mice showed impaired hypersensitivity responses, strongly reduced cartilage destruction in an arthritis model, and impaired protection from a bacterial infection. We conclude that FcγRI contributes substantially to a variety of IgG2a-IC-dependent immune functions and immunopathological responses.