Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Neutrophil-associated inflammation or microthrombus formation (Immunothrombosis) in the lung resulted in acute respiratory distress syndrome, the most important cause of death in septic multiple organ failure. Histidine-rich glycoprotein (HRG) is a 75 kDa glycoprotein mainly produced by liver. HRG is known as the plasma factor to regulate coagulation/fibrinolysis, immune response and angiogenesis. Our recent studies revealed that plasma HRG levels significantly decreased in cecal ligation puncture (CLP) septic mice model and administration of HRG dramatically improved the survival rate of CLP mice associated with the inhibition of immunothrombosis and neutrophil extracellular trap formation in pulmonary vasculatures by keeping neutrophils quiescent morphologically and functionally, and the protection of vascular endothelial cells and inhibition of erythrocyte aggregation. Thus, HRG-supplementary therapy may provide a novel strategy for the treatment of septic patients.