Caveolin-1, the major structural protein of caveolae, is present in several cell types known to play a role in the development of atherosclerosis. In this study, the distribution and expression of caveolin-1 in the arterial walls were studied in hypercholesterolemic rabbits. Immunohistochemical results indicated that the staining intensity of caveolin-1 reached a high level in the arterial intima at 5 weeks after high-cholesterol-diet treatment and decreased to a very low level at 8 weeks when atheromatous plaques appeared. Western blot analysis showed that in rabbits fed a high-cholesterol diet for 5 weeks, the expression of caveolin-1 reached its highest level and then decreased from 8 to 12 weeks. The proliferative activity of smooth muscle cells (SMCs) decreased to the lowest level at 5 weeks and then increased at 8 and 12 weeks. Nitric oxide synthase activity gradually decreased in animals fed a high-cholesterol diet throughout the experiment. These studies demonstrate that the change in abundance of caveolin-1 is associated with SMC proliferation in the formation of atheromatous plaque after hypercholesterolemia insult.