To elucidate the pathophysiologic mechanisms of transluminal angioplasty, normal coronary arteries in dogs, atherosclerotic human coronary arteries, and atherosclerotic vessels in rabbits were studied after angioplasty. Normal canine coronary arteries showed desquamation of endothelium, exposure of subendothelial connective tissue elements, and deposition of a carpet of platelets, fibrin, and occasional red blood cells. Administration of low molecular weight dextran before angioplasty decreased platelet deposition. Atherosclerotic human coronary arteries studied postmortem showed enlargement of lumen size after angioplasty due to splitting and disruption of the plaque and the underlying media. Endothelial desquamation and splitting of the plaque were also seen in atherosclerotic vessels in rabbits after angioplasty. The amount of splitting seems to depend on the relative size of the stenotic vessel and the inflated angioplasty balloon. Animals studied sequentially showed retraction of the separated intimal plaque elements and further lumen enlargement after 1-2 weeks. Two mechanisms of successful angioplasty are suggested by these studies: (1) desquamation of superficial plaque elements and (2) splitting of the plaque with retraction of intimal flaps as healing occurs. These mechanisms have important implications for the treatment of patients undergoing percutaneous transluminal angioplasty.