To study the effect of the severe loss of hepatic synthetic function on the inhibitors of coagulation we have measured protein S (total and free), protein C, heparin cofactor II and antithrombin III in 30 patients with fulminant hepatic failure. The results showed severe reduction in all inhibitor levels with mean (+/- SE) values of: protein S, 0.26 +/- 0.03 U/ml; protein C, 0.26 +/- 0.03 U/ml; heparin cofactor II, 0.12 +/- 0.02 U/ml and antithrombin III, 0.21 +/- 0.02 U/ml. Heparin cofactor II was significantly lower than the other inhibitors (P less than 0.01). Although the reduction in free protein S was significant in fulminant hepatic failure as compared to normal subjects (0.40 +/- 0.05 U/ml compared to 1.02 +/- 0.08 U/ml, P less than 0.001), the ratio of free to total protein S was significantly increased (0.67 +/- 0.02 compared to 0.40 +/- 0.04, P less than 0.01). Prothrombin time (INR) was significantly inversely correlated with total protein S (r = -0.56, P less than 0.001) and free protein S (r = -0.48, P less than 0.01), but not with the ratio of free to total protein S. No significant correlation between the different coagulation inhibitors and other measures of hepatic function could be detected. Although the loss of hepatic synthetic function appears to be the major cause of the loss of coagulation inhibitors, other effects such as increased consumption and rate of clearance may play a role. The balance of these will be reflected in the circulating levels of the coagulation inhibitors.