Purpose: The aim of this study was to explore the possible etiologic relationship of hypercholesterolemia and atherosclerosis to corporal veno-occlusive dysfunction. Materials and Methods: In the New Zealand White rabbit, the competence of the corporal veno-occlusive mechanism was examined at various intervals after exposure to control diet, high cholesterol diet, or aortoiliac atherosclerosis. Results: Initially, all animals showed normal erectile function and corporal veno-occlusion After 8 weeks and 16 weeks, the control animals preserved normal erection and corporal veno-occlusion, while most of the hypercholesterolemic and atherosclerotic animals developed corporal veno-occlusive dysfunction. The incidence of corporal veno-occlusive dysfunction in the hypercholesterolemia and atherosclerotic animals increased with time. Conclusions: This study suggests that a close relationship exists between prolonged atherosclerotic occlusion of major penile arteries and the development of corporal veno-occlusive dysfunction. Ischemia-induced corporal veno-occlusive dysfunction may be the result of alterations in corporal smooth muscle relaxation or changes in the structure and fibroelastic properties of erectile tissue.