Previous studies from this laboratory have shown that oxidative modification of low-density lipoprotein (LDL) causes it to be recognized by the scavenger receptor of the macrophage. Consequently, the rate of degradation of oxidized LDL by macrophages can be 3 to 10 times that of native LDL. Antioxidants, such as probucol, are highly effective in preventing the oxidative modification of LDL. Our recent studies show that probucol treatment of LDL receptor-deficient Watanabe heritable hyperlipidemic (WHHL) rabbits selectively inhibits the degradation of LDL in fatty streak lesions (which are rich in macrophage-derived foam cells) without inhibiting degradation in nonlesioned areas (where degradation is predominantly in smooth muscle cells, which do not express the scavenger receptor). Furthermore, the rate of progression of lesions in probucol-treated animals was significantly slower than in a lovastatin-treated group maintained at equal total plasma cholesterol levels. These results strongly suggest that probucol, through an antioxidant activity not necessarily related to its ability to lower plasma cholesterol levels, can slow the progression of the foam-cell-rich fatty streak lesion of atherosclerosis.