Restenosis is a frequent long-term complication after balloon angioplasty. Although smooth muscle cells form the major constituent of the occluding lesion, macrophage-derived foam cells are usually also present in high abundance. The latter have the potential to accelerate the rate of reocclusion because they elaborate many potent cytokines and growth factors, which may act to either recruit cells into the neointima or cause neointimal cell proliferation. Macrophage-derived foam-cell formation depends upon the uptake of modified low density lipoprotein via a scavenger receptor-mediated pathway. Foam-cell formation is accompanied by the release of smooth muscle cell mitogens and chemoattractants. We have examined the effects of probucol, a lipid-soluble antioxidant, in the balloon-catheterized carotid artery of the cholesterol-fed rabbit to evaluate the importance of oxidative processes in restenosis. After 5 weeks, serum cholesterol levels were 32% lower (P < 0.05) in rabbits fed 1% probucol with 2% cholesterol, compared with those receiving cholesterol alone. Probucol inhibited neointimal macrophage accumulation by 68% (P < 0.001), reduced absolute intimal size by 51% (P < 0.05), and reduced the intima/media thickness ratio by 51%. These inhibitory effects were directly related to serum probucol concentrations and appeared to be unrelated to probucol's hypocholesterolemic activity. These data suggest that reactive oxygen species may be involved in the intimal response to injury and that antioxidants, such as probucol, may be therapeutically useful as inhibitors of restenosis.