To understand the rationale for the determination of HMGB1 levels in human plasma, we briefly summarize the role of HMGB1 protein in the cell and outside the cell (extracellular HMGB1), to support the idea of the functioning of the extracellular HMGB1 as a biomarker for survival and treatment success of patients with inflammation-mediated diseases, including COVID-19. This evidence concerns the gene HMGB1 and COVID-19.