Purpose: The efficacy of carotid endarterectomy (CEA) for prevention of stroke has been demonstrated in randomized trials; however, the optimal approach in patients excluded from these trials or who have other significant comorbid conditions remains controversial, particularly with the advent of percutaneous interventions. We examined the influence of putative risk factors on outcome of CEA in a single-center experience. Methods: A retrospective analysis of 1370 consecutive CEA performed from 1990 to 1999 was undertaken. Preoperative risk factors examined included age older than 80 years, congestive heart failure, chronic obstructive pulmonary disease, renal failure (serum creatinine concentration > 2.0 mg/dL), contralateral carotid artery occlusion, recurrent ipsilateral carotid artery stenosis, ipsilateral hemispheric symptoms within 6 weeks, and recent coronary bypass grafting (CABG). The Fisher exact test was used to identify baseline variables associated with perioperative (30 days) risk for stroke or death. Multivariate analysis with Poisson regression was used to study the effect of all univariate criteria in combination. Results: In the overall cohort, there were 32 adverse events (2.3%), including 11 deaths (0.8%), 6 disabling strokes (0.4%), and 10 nondisabling strokes (0.7%). There was no significant difference in incidence of perioperative stroke or death between patients with one or more risk factors (n = 689) and those with no risk factors (low risk, n = 681). Thirty-day mortality was significantly greater in patients with two or more risk factors compared with patients with no risk factors (2.8% vs 0.3%; P = .04), but no significant difference was noted in perioperative stroke rate (2.3% vs 1.0%). Univariate analysis demonstrated that contralateral carotid occlusion (n = 75) was the only significant predictor of adverse outcome (5 events, 6.7%) among the variables tested; this was confirmed with multivariate analysis (relative risk, 4.3; 95% confidence interval, 1.2-12.3; P = .01). Five-year survival for patients with two or more risk factors was notably diminished compared with that for patients with no risk factors (38.7% ± 5.9% vs 75.0% ± 2.6%; P < .001). Contralateral occlusion was also associated with reduced 5-year survival (38 ± 11% vs 67 ± 2%; P < .004). Conclusion: CEA can be safely performed in patients deemed at high risk, including those aged 80 years or older and others with significant comorbid conditions, with combined stroke and mortality rates comparable to those found in randomized trials, ie, the Asymptomatic Carotid Atherosclerosis Study and the North American Symptomatic Carotid Endarterectomy Trial. Contralateral occlusion may be a predictor for moderately increased perioperative risk and for reduced long-term survival. Caution may be warranted in asymptomatic patients with multiple risk factors, in whom presumed long-term benefit of CEA may be compromised by markedly reduced 5-year survival.