Hepatic vein thrombosis initiated by an intravenous injection of endotoxin (Salmonella typhosa, 0.3 mg/kg) resulted in an incidence of 78% in rats fed a butter-rich diet (group 1). On the other hand, no lesion could be produced in control animals fed corn oil (group 2) or standard chow (group 3). In regard to the respective thrombotic tendencies, the rats fed butter showed higher circulating levels of factor XII (175% vs 140% in group 2 and 100% in group 3) and a far more severe decrease in this factor (41% vs 15% in group 2 and 7% in group 3) and in platelets (48% vs 25% in group 2 and 19% in group 3) 2 hours after the injection of endotoxin. The triggering effect of endotoxin could be reproduced by ellagic acid, a known activator of factor XII. Given by slow infusion (1 mg/kg/min) this chemical induced hepatic vein thrombosis in 52% of the rats fed the butter-rich diet. Furthermore, inhibition of factor XII activation by lysozyme (20 mg/kg/min) completely prevented hepatic vein thrombosis initiated by endotoxin in butter-fed animals. It is concluded that, in addition to the potent hypercoagulability induced by the fat-rich diets, activation of Hageman factor consecutive to endotoxin injection is essential for production of the phenomenon of hepatic vein thrombosis.