This study was designed to clarify the effects of vitamin E on the alterations in proteoglycan distribution and vascular permeability, which were examined by immunohistochemical and ultrastructural techniques in the aortas of cholesterol-fed guinea pigs. The animals were divided into three groups: a control group, a cholesterol group, and a vitamin E group. Serum levels of cholesterol, triglyceride, low-density lipoprotein, high-density lipoprotein, and thiobarbituric acid-reactive substances were measured. An increase in thiobarbituric acid-reactive substances was observed in the cholesterol group compared with control and vitamin E groups. Intimal atheromatous lesions of the aorta were significantly decreased in the vitamin E group compared with the cholesterol group. Histochemically, an increased distribution of proteoglycans such as chondroitin, dermatan, and heparan sulfates and ruthenium red reaction products in the intima; decreased glycocalyx on the endothelial surface; and increased permeability to horseradish peroxidase were revealed in the cholesterol group compared with the vitamin E group. Hypercholesterolemia, resulting in superoxide production, may have contributed to the endothelial damage and increased permeability to plasma proteins and lipids in the vascular wall of the cholesterol group. However, vitamin E administration inhibited lipid deposition and development of this abnormal permeability associated with an irregular distribution of proteoglycan. These results suggest that vitamin E preserves the morphological and functional integrity of the vascular wall and may contribute to the inhibition of atherogenesis in cholesterol-fed guinea pigs.