Circulating SARS-CoV-2+ megakaryocytes associate with severe viral infection in COVID-19. A subpopulation of proinflammatory megakaryocytes (MK) is identified in the peripheral blood of patients with COVID-19 with severe manifestations. These cells contain calprotectin heterodimers (S100A8/A9), present interferon response and inflammatory cytokines signatures, and are activated. SARS-CoV-2 can be found in megakaryocytes. SARS-CoV-2 protein and RNA (a whole virus is illustrated, although the presence of actual virions in circulating megakaryocytes is hypothetical and is not shown in this study). The number of SARS-CoV-2-containing megakaryocytes strongly correlates with risk factors such as mortality and multiorgan injury. A combination of experimental approaches is needed to confirm the presence of megakaryocytes. Professional illustration by ScEYEnce Studios.