In patients with severe COVID-19, multiorgan damage occurs due to the massive induction of various types of cell death (necrosis, apoptosis, iron-dependent lipid peroxidation-induced ferroptosis, pyroptosis) associated with the large release of HMGB1, which is responsible for the development of epithelial barrier failure, organ dysfunction, and even death. This evidence concerns the gene HMGB1 and COVID-19.