In the present study we investigated the therapeutic action of antithrombin III (AT III) in taurocholate-induced experimental pancreatitis with high lethality in rats. High-dose AT III treatment greatly improved the survival rate not only when given as pretreatment but also when given 2 hr after induction. No favorable effect on survival rate was observed on administration after 5 hr. Both intravascular and intraperitoneal AT III administration locally restored decreased AT III levels in the peritoneal cavity and increased plasma AT III to supranormal levels. The primary pancreatic insult seemed to be unaffected by the treatment, because neither the rise in plasma lipase nor the development of ascites or the extension of the pancreatic necrosis were diminished. Because heparin pretreatment of the rats was also effective, the mechanism of the beneficial action was probably mediated by inhibition of the proteases of the coagulation cascade, thereby preventing intravascular coagulation in the pancreas and distant organs and subsequent systemic complications. The high efficacy of AT III treatment in this experimental model may stimulate clinical studies evaluating the efficacy of AT III treatment in an early stage of acute pancreatitis.