Protein C, a naturally occurring inhibitor of blood coagulation, was measured immunologically in 160 patients with acute and chronic liver and biliary disease. In 31 patients with acute viral hepatitis serially studied from admission to discharge from hospital, protein C antigen (PC:Ag) was low on admission in a high proportion of cases (61%) but became normal in 90% of them after two weeks at a time when the prothrombin time was still prolonged in 46% of the cases. PC:Ag was also low in 25 cirrhotic patients and in 20 patients with chronic active hepatitis. In chronic hepatitis and cirrhosis, PC:Ag levels significantly correlated with indexes of liver synthetic function. In primary biliary cirrhosis (n:40), PC:Ag was low in patients with advanced disease (stages III-IV) but high in the early phases, when cholestasis was not yet accompanied by impaired protein synthesis. PC:Ag was also very high in 20 patients with large bile duct obstruction and highly correlated with indexes of cholestasis. The authors' findings indicate that PC:Ag is reduced in liver disease proportionally to the impairment of the liver synthetic function and that its normalization after acute hepatitis might represent an early marker of recovery of this function.