Abstract Vitamin E has been postulated to be antiatherogenic because of its antioxidative potency. However, intervention studies published to date have yielded conflicting results. To assess the antiatherogenic effect of vitamin E, two groups of 10 Watanabe heritable hyperlipidemic (WHHL) rabbits each were fed chow pellets containing D-α-tocopherol-acetate at either 40 mg/kg (control group) or 1000 mg/kg (vitamin E group) for 28 weeks. Plasma vitamin E levels in the vitamin E group were increased five-fold over those in controls (475.5 μmol/l vs. 95.9 μmol/l). The average total plasma cholesterol during the treatment period was not significantly affected by vitamin E (control, 950 ± 113 mg/dl; vitamin E, 884 ± 90 mg/dl). Vitamin E treatment had no significant effects on body weights, lipoprotein profiles, or HDL levels. The protection of plasma LDL against oxidation was determined ex vivo by measuring the lag time in the formation of conjugated dienes in a standardized Cu 2+-containing system. Lag time in the vitamin E-treated group increased four-fold over that in controls (404 vs. 123 min). The extent of atherosclerosis determined at the end of the study was not significantly different in the two groups (control group, 59.2 ± 6.0%; vitamin E group, 50.6 ±6.2%, P = 0.33). Analysis of the correlation between vitamin E levels and extent of lesions also failed to indicate an antiatherosclerotic effect of vitamin E treatment. We previously reported that an analogue of probucol that provided antioxidative protection similar to that provided by vitamin E failed to prevent atherogenesis in WHHL-rabbits. In contrast probucol conveyed a much greater degree of antioxidant protection and effectively reduced atherosclerosis in rabbits. The results of the present study therefore support the hypothesis that a threshold level of antioxidative protection of LDL may be required to inhibit atherosclerosis.