A rabbit model in which intrinsic clotting was selectively impaired by injection of a human factor VIII antibody was used to evaluate the mechanism of endotoxin-induced intravascular clotting in cortisone-treated rabbits. Three groups of animals were studied: a control group given factor VIII antibody followed by saline; a second control group given an inert material followed by endotoxin; and an experimental group given factor VIII antibody followed by endotoxin. The following parameters were measured: 125I-fibrinogen kinetics, fibrinogen levels, factor VIII, factor VII, factor V, WBC, platelets, and hematocrit. The kidneys were examined for deposition of fibrin. Mean values for factor VIII at the time of injection of the second test material and mean values for fibrinogen consumed in the 6 hr after the second injection were as follows: antibody-saline group, 8.5% and 11.0 mg/kg; control material-endotoxin group, 90% and 29.6 mg/kg; and antibody endotoxin group, 7.0% and 32.7 mg/kg. Factor V, factor VII, granulocytes, and platelets fell in both groups of animals given endotoxin. One animal in each group given endotoxin developed gross renal cortical necrosis. These data establish that selective impairment of the intrinsic clotting reactions does not reduce the amount of clotting induced by a single injection of endotoxin in the cortisone-treated rabbit.