Purpose: Given the uncertainties associated with carotid angioplasty and stenting, the initial assessment of the procedure may be best undertaken in a subgroup of patients at increased risk for complications with standard carotid surgery. In an effort to characterize such a subgroup, we reviewed the results of carotid endarterectomy in patients with and without significant medical comorbidity. Methods: During a 10-year period 3061 carotid endarterectomies were performed at a single institution and entered prospectively into a registry. A high-risk patient subgroup was identified, defined by the presence of severe coronary artery disease, chronic obstructive lung disease, or renal insufficiency. The outcome of carotid endarterectomy was assessed with respect to perioperative stroke, myocardial infarction, or death, as well as the combined end point of one or more of the end points. Results: The rate of the composite end point stroke/myocardial infarction/death was 3.8% in the total group of 3061 patients who underwent endarterectomy. As individual end points, the rate of stroke was 2.1%, myocardial infarction 1.2%, and death 1.1%. Among the high-risk subset, the composite end point stroke/myocardial infarction/death occurred in 7.4%. This rate was significantly greater than the corresponding rate of 2.9% in the low-risk subset (P < .0005). Similarly, the rate of stroke (3.5% vs 1.7%, P = .008) or death (4.4% vs 0.3%, P < .001) as solitary events was significantly greater in high-risk patients. Conclusions: Although carotid endarterectomy is an extremely safe procedure in most patients, results are not as favorable in a high-risk subset with severe coronary, pulmonary, or renal disease. The initial clinical evaluation of carotid stenting might best be undertaken in such a high-risk population, one that comprises patients for whom standard therapy is associated with a high rate of complications. (J Vasc Surg 2001;33:728-32.).