Complement and Fcγ receptor (FcγR) effector pathways are central triggers of immune inflammation; however, the exact mechanisms for their cooperation with effector cells and their nature remain elusive. Here we describe a novel regulatory crosstalk between complement and FcγRs on macrophages as the dominant event in the Arthus reaction, the classical animal model of immune complex disease. Specifically, initial contact between immune complexes and macrophages results in cellular regulation: plasma complement-independent C5a production; selective G_i-dependent C5aR signaling; and C5aR-G_i-mediated FcγR alterations towards Fc RIII, the previously shown main inducer of tumour necrosis factor alpha and CXCR2 ligand production. Distinct inhibitors of this refined inflammatory cascade are each effective in disease prevention, thus indicating cellular components of the C5aR–FcγR axis as potential new therapeutic targets in the treatment of inflammation and autoimmune diseases.