This study investigates the role of neutrophil extracellular traps (NETs) in severe cases of COVID-19. NETs are extracellular webs composed of chromatin, microbial proteins, and oxidant enzymes released by neutrophils to contain infections. However, when not properly regulated, NETs can contribute to inflammation and microvascular thrombosis. The researchers found that sera from COVID-19 patients had elevated levels of cell-free DNA, myeloperoxidase-DNA (MPD-DNA), and citrullinated histone H3 (Cit-H3), which are specific markers of NETs. These markers correlated with acute-phase reactants such as C-reactive protein, D-dimer, and lactate dehydrogenase, as well as absolute neutrophil count. Notably, cell-free DNA and MPD-DNA were higher in hospitalized patients receiving mechanical ventilation compared to those breathing room air. Additionally, COVID-19 sera triggered NET release from control neutrophils in vitro. The findings suggest that NETs may play a significant role in the progression of severe COVID-19 and could be novel therapeutic targets. Future studies should investigate the predictive power of circulating NETs in longitudinal cohorts and explore potential therapeutic strategies targeting NETs in severe COVID-19.This study investigates the role of neutrophil extracellular traps (NETs) in severe cases of COVID-19. NETs are extracellular webs composed of chromatin, microbial proteins, and oxidant enzymes released by neutrophils to contain infections. However, when not properly regulated, NETs can contribute to inflammation and microvascular thrombosis. The researchers found that sera from COVID-19 patients had elevated levels of cell-free DNA, myeloperoxidase-DNA (MPD-DNA), and citrullinated histone H3 (Cit-H3), which are specific markers of NETs. These markers correlated with acute-phase reactants such as C-reactive protein, D-dimer, and lactate dehydrogenase, as well as absolute neutrophil count. Notably, cell-free DNA and MPD-DNA were higher in hospitalized patients receiving mechanical ventilation compared to those breathing room air. Additionally, COVID-19 sera triggered NET release from control neutrophils in vitro. The findings suggest that NETs may play a significant role in the progression of severe COVID-19 and could be novel therapeutic targets. Future studies should investigate the predictive power of circulating NETs in longitudinal cohorts and explore potential therapeutic strategies targeting NETs in severe COVID-19.