To investigate the cellular reactions to arterial injuries and the influence of a cholesterol-rich diet, 18 rabbits underwent endothelial denudation of the abdominal aorta with a balloon catheter. Fourteen animals were fed a 2% cholesterol diet and 4 were fed normal rabbit chow for 8 weeks. In the cholesterol-fed group, 6 animals had only the expected intimal lesions; however, 8 animals exhibited different degrees of balloon-induced medial layer injury, with fibrous healing. Similarly, in the control rabbits, 1 had intimal lesions and 3 had both intimal and medial layer lesions. We conclude that removal of the endothelium with a balloon catheter promotes arterial wall injury deeper than expected. This unexpected result could influence the effect of interventions usually employed in experimental atherosclerosis.