In the current study, we demonstrated that HMGB1 has two LPS-binding motifs located in its A and B box domains respectively, and that two synthetic peptides (HPep1 and HPep6) containing each of these LPS-binding motifs respectively, can inhibit LPS-stimulated TNF-α production both ex vivo in human PBMCs and in vivo in a mouse model of subclinical endotoxemia. The gene discussed is TNF; the disease is serum lipopolysaccharide activity.