The IgA Fc receptor (FcαRI) has dual proinflammatory and anti-inflammatory functions that are transmitted through the immunoreceptor tyrosine-based activation motifs (ITAMs) of the associated FcRγ subunit. Whereas the involvement of FcαRI in inflammation is well documented, little is known of its anti-inflammatory mechanisms. Here we show that monomeric targeting of FcαRI by anti-FcαRI Fab or serum IgA triggers apoptosis in human monocytes, monocytic cell lines, and FcαRI+ transfectants. However, the physiologic ligand IgA induced apoptosis only when cells were cultured in low serum conditions, indicating differences with induction of anti-inflammatory signaling. Apoptosis signaling required the FcRγ ITAM, as cells transfected with FcαRI or with a chimeric FcαRI-FcRγ responded to death-activating signals, whereas cells expressing a mutated FcαRIR209L unable to associate with FcRγ, or an ITAM-mutated chimeric FcαRI-FcRγ, did not respond. FcαRI-mediated apoptosis signals were blocked by treatment with the pan-caspase inhibitor zVAD-fmk, involved proteolysis of procaspase-3, and correlated negatively with SHP-1 concentration. Anti-FcαRI Fab treatment of nude mice injected subcutaneously with FcαRI+ mast-cell transfectants prevented tumor development and halted the growth of established tumors. These findings demonstrate that, on monomeric targeting, FcαRI functions as an FcRγ ITAM-dependent apoptotic module that may be fundamental for controlling inflammation and tumor growth.