In this study, we asked the question "does ␣ -tocopherol supplementation prevent an increase in total plasma cholesterol (TPC) concentration and reduce the deposition of cholesterol in arterial plaques of rabbits fed atherogenic diets?" Isocaloric diets containing 0.1% cholesterol to induce atherosclerosis were enriched in one of three fats: saturated fats (SAT), monounsaturated fats (MONO), or n-6 polyunsaturated fats (POLY). Half of each of the three diets were supplemented with 2,500 IU ␣ -tocopherol/kg-diet. Unsupplemented diets contained 25 IU ␣ -tocopherol/kg-diet. Rabbits supplemented with ␣ -tocopherol had plasma ␣ -tocopherol concentrations 10-fold higher and an average TPC concentration 31% lower, P ؍ 0.017, than rabbits fed unsupplemented diets. Among the three fat-fed groups, the difference was greatest for the POLY fat fed group (54%, P ؍ 0.041). POLY fat-fed rabbits without ␣ -tocopherol supplementation had plasma HDL cholesterol concentrations that were less than half that of rabbits fed other fats, P р 0.0001. In general, differences in mean esterified artery cholesterol concentrations among the three fat-fed groups, with and without ␣ -tocopherol supplementation, paralleled differences in TPC concentration among the groups.This study suggests that for rabbits fed high pharmacological doses of ␣ -tocopherol, atherosclerosis can be diminished in situations where the plasma cholesterol concentrations are also significantly lower. -Schwenke, D. C., L. L. Rudel, M. G. Sorci-Thomas, and M. J. Thomas. ␣ -Tocopherol protects against diet induced atherosclerosis in New Zealand white rabbits.