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 conjugateddiene formation of LDL subjected to in vitro oxidation by 54% (P<.00l) and 51% (P=.O19), respectively. In this LDL-oxidizability assay, only vitamin E reduced the maximal rate of conjugated-diene production (-24%, P<.001). Neither vita- showing that probucol attenuates the progression of atherosclerotic lesion formation in Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model for familial hypercholesterolemia, provided strong evidence that lipid peroxidation plays a prominent role in atherogenesis. On the basis of these studies and others, 35 a lipid peroxidation hypothesis has been developed to explain the process of atherogenesis in humans.6 Central in this hypothesis is the oxidation of low-density lipoproteins (LDLs), leading to characteristic physicochemical modifications. Once LDL is modified, unlimited amounts are taken up through the scavenger receptor of macrophages present in the arterial intima. The excessive accumulation of cholesterol in macrophages results in their transformation to foam cells, the hallmark of atherosclerotic lesion formation.LDL contains several natural antioxidants that provide protection against excessive oxidative modification.