Use of the antioxidant probucol has been associated with a reduction in the development of atherosclerotic lesions in Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model of familial hypercholesterolemia. In this study, atheromatous lesions from control or probucol-treated WHHL rabbits were probed with monoclonal antibodies to evaluate whether use of this drug either affected the presence or distribution of epitopes recognized by an antibody against oxidized low density lipoprotein or altered the cellular makeup of lesions. Although probucol-treated animals had much less aortic atherosclerosis than did controls, equivalent immunoreactivity for the anti-oxidized LDL antibody (OXL 41.1) was demonstrated in atherosclerotic lesions of both groups of animals, consistent with a role for oxidative modification of lipoproteins in atherogenesis in this animal model. Use of smooth muscle cell-specific (HHF-35) and macrophage-specific (RAM-11) antibodies demonstrated that lesions from probucol-treated animals were significantly smaller (p less than 0.01) and less cellular (p less than 0.05) than were control lesions. In addition, smooth muscle cells were the predominant cell type in lesions from probucol-treated animals, whereas macrophages predominated in lesions from controls (p less than 0.01). These findings are consistent with a reduction of monocyte/macrophage recruitment into or retention in lesions in probucol-treated animals, or with probucol-induced alterations in the production of growth factors or cytokines that might influence the cellular makeup of atherosclerotic lesions.