Sulindac (SLD) is a nonsteroidal anti-inflammatory drug (NSAID) that has been associated with a greater incidence of idiosyncratic hepatotoxicity in human patients than other NSAIDs. One hypothesis regarding idiosyncratic adverse drug reactions is that interaction of a drug with a modest inflammatory episode precipitates liver injury. In this study, we tested the hypothesis that lipopolysaccharide (LPS) interacts with SLD to cause liver injury in rats. SLD (50 mg/kg) or its vehicle was administered to rats by gavage 15.5 h before LPS (8.3 x 10(5) endotoxin unit/kg) or its saline vehicle (i.v.). Thirty minutes after LPS treatment, SLD or vehicle administration was repeated. Rats were killed at various times after treatment, and serum, plasma, and liver samples were taken. Neither SLD nor LPS alone caused liver injury. Cotreatment with SLD/LPS led to increases in serum biomarkers of both hepatocellular injury and cholestasis. Histological evidence of liver damage was found only after SLD/LPS cotreatment. As a result of activation of hemostasis induced by SLD/LPS cotreatment, fibrin and hypoxia were present in liver tissue before the onset of hepatotoxicity. Heparin treatment reduced hepatic fibrin deposition and hypoxia and protected against liver injury induced by SLD/LPS cotreatment. These results indicate that cotreatment with nontoxic doses of LPS and SLD causes liver injury in rats, and this could serve as a model of human idiosyncratic liver injury. The hemostatic system is activated by SLD/LPS cotreatment and plays an important role in the development of SLD/LPS-induced liver injury.