A prospective study of carotid endarterectomy specimens showed an acute or recent intraplaque hemorrhage in 49 of 53 plaques (92.5%) from symptomatic patients, compared with seven of 26 plaques (27%) from nonsymptomatic patients. Luminal stenosis of greater than 50% was noted in 46 of 53 symptomatic patients (75%), 43 of whose plaques had evidence of multiple hemorrhages. Intimal disruption (ulceration) occurred over protruding mounds of intraplaque hemorrhage and was associated with retinal cholesterol emboli and prolonged neurologic deficits. Mural recesses with the angiographic appearance of ulceration seldom showed intimal breakdown. Eighteen patients continued to have symptoms while receiving aspirin, 13 of whom had had multiple intraplaque hemorrhages. Angioneogenesis occurred within the plaques in response to hemorrhage, creating vascular lesions vulnerable to mechanical stress and capable of producing further hemorrhage or intimal disruption.