This study supplied evidence that the presence of severe headache in COVID-19 was associated with elevated inflammatory and/or nociceptive molecules like HMGB1, NLRP3, IL-6, and ACE2 compared to the non-headache COVID-19 sufferers, while anti-inflammatory cytokine levels of IL-10 did not show any difference at hospital admission between the two groups. This evidence concerns the gene HMGB1 and COVID-19.