Abstract only Pathogen‐induced immune dysregulation is largely responsible for the morbidity and mortality associated with sepsis. Sepsis also involves inefficient bacterial clearance by phagocytic cells. Here we show that FcRγ, the ITAM‐bearing signal transduction subunit of the Fc receptor family, plays a deleterious role in sepsis. FcRγ−/− mice show increased survival during peritonitis, due to markedly increased E. coli phagocytosis and killing and to lower production of the pro‐inflammatory cytokine TNFα. The FcRγ‐associated receptor that inhibits E. coli phagocytosis is FcγRIII (CD16), and its absence protects mice from sepsis. CD16 binds E. coli, and this interaction induces FcRγ phosphorylation, SHP‐1 recruitment and PI3‐K dephosphorylation. Decreased PI3‐K activity inhibits E. coli phagocytosis and increases TNFα production through TLR4. We identified the phagocytic receptor negatively regulated by FcRγ on macrophages as the class A scavenger receptor MARCO. E. coli‐CD16 interaction induces the recruitment of SHP‐1 to MARCO, thereby inhibiting E. coli phagocytosis. Thus, by binding CD16, E. coli triggers an inhibitory FcRγ pathway that both impairs MARCO‐mediated bacterial clearance and activates TNFα secretion. This mechanism could be the target of new therapeutic approaches in sepsis. Granted by Inserm, ANR‐Mime and FAPESP.