Circulating and hepatic interleukin (IL)-6 levels are strongly increased during clinical and experimental cholestasis. Cholestatic liver injury is associated with an increased susceptibility to endotoxin-induced toxicity. To determine the role of IL-6 herein, extrahepatic cholestasis was induced by bile duct ligation (bdl) in IL-6-gene deficient (IL-6-/-) and normal IL-6+/+ mice. Bdl elicited increased levels of hepatic IL-6 mRNA and protein in normal mice. Hepatocellular injury at 2 weeks after bdl was similar in IL-6-/- and IL-6+/+ mice as demonstrated by clinical chemistry and histopathology. Administration of endotoxin to cholestatic mice at 2 weeks after bdl was associated with enhanced cytokine release, severe liver damage and death when compared to sham-operated mice. Effects of endotoxin were largely similar in sham-operated IL-6-/- and IL-6+/+ mice, but cholestatic IL-6-/- mice were more susceptible to the toxic effects of endotoxin, as reflected by increased cytokine release, more profound liver injury and lung inflammation and higher mortality. Although endogenous IL-6 is not important in the development of liver injury after experimentally induced obstructive jaundice, this cytokine plays an important role in decreasing hypersensitivity to endotoxin in cholestatic mice.