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This article assessed whether plasma collected from patients with COVID-19 at different disease stages could trigger endothelial damage in vitro by using cultured human pulmonary microvascular endothelial cells (HPMVEC) This study also further investigated the association of plasma-induced cytotoxicity with levels of circulating biomarkers related to organ dysfunction (Pao2 [partial pressure of oxygen in arterial blood]/Fio2 [fraction of inspired oxygen], widely used as an indicator of oxygenation requirements, lactate dehydrogenase, creatinine, and aspartate transaminase), endothelial damage (von Willebrand factor antigen;ADAMTS13;plasminogen activator inhibitor-1;syndecan-1), tissue injury (cell-free DNA, a damage-associated molecular patterns marker), and levels of circulating cytokines related to the activation of innate (interleukin [IL]-6 and tumor necrosis factor-a) and adaptative immune cell responses (soluble IL-2 receptor) Inclusion criteria were individuals aged 18 years or older with a positive SARS-CoV-2 real-time reverse-transcriptase polymerase chain reaction on nasal or tracheal samples This data shed new light on the pathophysiology of COVID-19 by demonstrating the direct and rapid cytotoxic effect of plasma collected from critically ill patients on vascular endothelial cells This rapid effect (1 hour after plasma exposure) excludes a direct cytopathic effect of SARS-CoV-2 infection, as the progression of viral infection and visible cytopathogenic effects are in general only apparent 12 to 24 hours after infection 5 A higher cytotoxic effect of plasma on endothelial cells was associated with a more pronounced hypoxemia and organ dysfunction as reflected by the correlation with Pao2/FiO2, lactate dehydrogenase, creatinine, and aspartate transaminase This cytotoxic effect also correlated with circulating markers of endothelial damage, indicating that this in vitro functional assay reflects microvascular endothelial damage in vivo Different pathways could be involved in endothelial cell injury during the course of COVID-19, i e , complement activation, cellular hypoxia, platelets, and direct cytotoxicity of cytokines such as IL-6, IL-1beta, and tumor necrosis factor-a The study observed a relationship between this cytotoxic effect and the level of proinflammatory cytokines, suggesting that cytotoxicity could be related to overproduction of proinflammatory cytokines