Significance Immune complexes (ICs) form when antibodies encounter their antigens. ICs are present in blood in multiple pathological conditions. Given the abundance of platelets in blood and that they express a receptor for ICs, called Fcγ receptor IIA (FcγRIIA), we examined the impact of ICs in blood in a mouse model. We found that circulating ICs induced systemic shock, characterized by loss of consciousness, by activating platelet FcγRIIA. Shock was mediated by the liberation of serotonin, a molecule better known for its role in the brain, from platelet granules. During shock, platelets were sequestered in the lungs and brain and returned to the blood circulation after their degranulation. Platelets are thus crucial in response to ICs.