The diet of Watanabe heritable hyperlipidemic (WHHL) rabbits was supplemented with a low dose (0.025% [wt/wt]) of the antioxidant vitamin E or probucol. The effect of 6 months of treatment on the susceptibility of low-density lipoproteins (LDLs) to oxidative modification and on established atherosclerotic lesions was studied. Vitamin E administration had no effect on plasma lipid levels; probucol supplementation decreased plasma total cholesterol. Vitamin E levels in plasma and LDL increased threefold in the course of treatment with this antioxidant. Six months of treatment with vitamin E and probucol increased the lag time of conjugated-diene formation of LDL subjected to in vitro oxidation by 54% (P < .001) and 51% (P = .019), respectively. In this LDL-oxidizability assay, only vitamin E reduced the maximal rate of conjugated-diene production (-24%, P < .001). Neither vitamin E treatment nor probucol therapy reduced the amount of thiobarbituric acid-reactive substances in plasma. Vitamin E treatment reduced the specific LDL apolipoprotein B-100 fluorescence (-10%, P = .035) compared with controls. Probucol was without effect on this index of in vivo LDL oxidation. At the end of the 6-month study, the mean +/- SD percentage area of aorta covered with plaques was 58.7 +/- 10.1% in control animals, 62.7 +/- 12.0% in the probucol-treated animals, and 48.9 +/- 13.8% in the animals treated with vitamin E; these differences were not significant. This study demonstrates that at this low dosage, vitamin E is a more effective antioxidant than probucol.