The effects of highly purified ethyl ester of eicosapentaenoic acid (EPA-E) on ellagic acid-induced thrombus formation in the stenosed femoral artery in rabbits and on the progression of laurate-induced vascular lesions in rats were examined. (1) EPA-E in single administration significantly prevented the thrombus formation induced by ellagic acid in the stenosed femoral artery of rabbits. (2) EPA-E restored the hypercoagulation activity at 5 min and 3 hr after the ellagic acid injection. Platelet aggregability induced by arachidonic acid decreased at 5 min and 3 hr after the ellagic acid injection; EPA-E had little effect on this change. EPA-E showed almost no effect on fibrinolytic activity, blood viscosity and filterability of washed red blood cells after the ellagic acid injection. (3) Moreover, EPA-E in daily administrations showed a significant preventative effect against the laurate-induced vascular lesions in rats. The efficacy of EPA-E on arterial thrombosis and vascular lesions observed in this study suggests that EPA-E is a candidate for the treatment of peripheral circulatory disturbance.