In this study, levels of plasma alpha 2-Heremans-Schmid glycoprotein, serum tumor necrosis factor-a, serum liver function parameters and short-term mortality were measured in 100 hepatitis B patients. Release of interleukin-6 and tumor necrosis factor-a from the lipopolysaccharide-stimulated peripheral blood mononuclear cells in the presence/absence of spermine and alpha 2-Heremans-Schmid glycoprotein were analyzed by enzyme-linked immunosorbent assay to determine the significance and potential mechanism of alpha 2-Heremans-Schmid glycoprotein in hepatitis B virus-associated liver damage. Results showed that serum alpha 2-Heremans-Schmid glycoprotein levels in acute-on-chronic liver failure patients were significantly lower than that in chronic hepatitis B patients or healthy controls (p < 0.05). A negative dependence between serum human alpha 2-Heremans-Schmid glycoprotein and tumor necrosis factor-a levels was observed. Interleukin-6 and tumor necrosis factor-a levels in the lipopolysaccharide-induced peripheral blood mononuclear cell supernates were significantly reduced by spermine and/or alpha 2-Heremans-Schmid glycoprotein. The latter two proteins jointly inhibited cytokine release. These observations suggest that plasma alpha 2-Heremans-Schmid glycoprotein is an independent marker of liver damage and a prognostic indicator of hepatitis B virus chronicity. It may reduce liver inflammation by partially inhibiting release of inflammatory factors from activated peripheral blood mononuclear cells.