Severe COVID-19 patients develop acute respiratory distress syndrome that may progress to cytokine storm syndrome, organ dysfunction, and death . Considering that neutrophil extracellular traps (NETs) have been described as important mediators of tissue damage in inflammatory diseases, we investigated whether NETs would be involved in COVID-19 pathophysiology . A cohort of 32 hospitalized patients with a confirmed diagnosis of COVID-19 and healthy controls were enrolled . The concentration of NETs was augmented in plasma, tracheal aspirate, and lung autopsies tissues from COVID-19 patients, and their neutrophils released higher levels of NETs . Notably, we found that viable SARS-CoV-2 can directly induce the release of NETs by healthy neutrophils . Mechanistically, NETs triggered by SARS-CoV-2 depend on angiotensin-converting enzyme 2, serine protease, virus replication, and PAD-4 . Finally, NETs released by SARS-CoV-2-activated neutrophils promote lung epithelial cell death in vitro . These results unravel a possible detrimental role of NETs in the pathophysiology of COVID-19 . Therefore, the inhibition of NETs represents a potential therapeutic target for COVID-19.