1. Two experiments were conducted to determine whether or not high dietary levels of vitamin E affect the development of atherosclerotic lesions in aortas of cholesterol-fed (5 g/kg diet) rabbits that were mechanically deendothelialized by balloon catheterization. 2. In the first experiment, the aortas of rabbits fed 2000 mg vitamin E/kg diet (i.e. 50-fold their nutritional requirement) for 8 weeks showed no gross morphological differences, either within or outside experimentally damaged areas, from those of rabbits fed the nutritionally adequate control level (40 mg/kg) of the vitamin. 3. In the second experiment, rabbits fed 10,000 mg vitamin E/kg diet (i.e. 250-fold requirement) for 14-15 weeks showed significantly greater endothelial loss and plaque formation at aortic sites outside of the mechanically damaged area than did controls. Plasma cholesterol levels were very high (9000-14,000 mg/l) and were not affected by dietary vitamin E level until 10-12 weeks when they were reduced moderately (18%). 4. It is concluded that very high levels of vitamin E can potentiate spontaneous atherosclerotic lesions, and it is suggested that this effect may depend on high cholesterol status.