Objectives: The major forms of human inter-α-inhibitor proteins circulating in the plasma are inter-α-inhibitor (IαI, containing one light peptide chain called bikunin and two heavy chains) and pre-α-inhibitor (PαI, containing one light and one heavy chain). Although it has been reported that a decrease in IαI/PαI is correlated with an increased mortality rate in septic patients, it remains unknown whether administration of IαI/PαI early after the onset of sepsis has any beneficial effects on the cardiovascular response and outcome of the septic animal. The aim of this study, therefore, was to determine whether IαI and PαI have any salutary effects on the depressed cardiovascular function, liver damage, and mortality rate after polymicrobial sepsis. Design: Prospective, controlled, randomized animal study. Setting: A university research laboratory. Subjects: Male adult rats were subjected to polymicrobial sepsis by cecal ligation and puncture or sham operation followed by the administration of normal saline (i.e., resuscitation). Measurements and Main Results: At 1 hr after cecal ligation and puncture, human IαI/PαI at a dose of 30 mg/kg body weight or vehicle (normal saline, 1 mL/rat) were infused intravenously over a period of 30 mins. At 20 hrs after cecal ligation and puncture (i.e., the late, hypodynamic stage of sepsis), cardiac output was measured by using a dye dilution technique, and blood samples were collected for assessing oxygen content. Oxygen delivery, consumption, and extraction ratio were determined. Plasma concentrations of liver enzymes alanine aminotransferase and aspartate aminotransferase as well as lactate and tumor necrosis factor-α also were measured. In additional animals, the necrotic cecum was excised at 20 hrs after cecal ligation and puncture with or without IαI/PαI treatment, and survival was monitored for 10 days thereafter. The results indicate that administration of human IαI/PαI early after the onset of sepsis maintained cardiac output and systemic oxygen delivery, whereas it increased oxygen consumption and extraction at 20 hrs after cecal ligation and puncture. The elevated concentrations of alanine aminotransferase, aspartate aminotransferase, tumor necrosis factor-α, and lactate were attenuated by IαI/PαI treatment. In addition, administration of human IαI/PαI improved the survival rate from 30% to 89% in septic animals at day 10 after cecal ligation and puncture and cecal excision. Conclusion: Human IαI/PαI appears to be a useful agent for maintaining hemodynamic stability and improving survival during the progression of polymicrobial sepsis.