Recent studies have identified an aberrant myeloid cell activation programme in patients with COVID-19. In this preprint, Hoepel et al. elucidate a mechanism by which alveolar macrophages facilitate hyperinflammation. Serum IgGs, in complex with spike protein, from patients with severe COVID-19 were shown to induce a potent pro-inflammatory response in human macrophages through multiple FcγRs, but mainly through FcγRII. Blockade of this pathway using an inhibitor of the kinase SYK counteracted the pathological production of IL-6, IL-1β and TNF. Interestingly, in vitro exposure of endothelial cells to serum IgGs from these patients resulted in loss of barrier integrity and increased coagulopathy. These results improve our understanding of the abnormal myeloid response in COVID-19 and identify a potential therapeutic target.