Background Cerebrovascular accidents (CVAs), transient ischemic attacks (TIAs), and peripheral arterial disease (PAD) frequently coexist with coronary artery disease (CAD) and were previously reported to adversely affect the prognosis of patients with chronic CAD. Methods We examined the effect of prior CVA/TIA or PAD (extra-cardiac vascular disease [EVD]) on the outcome of 10,281 patients with acute coronary syndromes enrolled in the Orbofiban in Patients with Unstable Coronary Syndromes-Thrombolysis in Myocardial Infarction (OPUS-TIMI) 16 trial of the oral glycoprotein IIb/IIIa antagonist orbofiban plus aspirin versus aspirin alone. We evaluated mortality, recurrent cardiac events, and stroke and used multivariate analysis to control for differences in baseline characteristics. Results Patients with EVD were older, had more coronary risk factors, had a history of CAD, and received more intensive medical treatment at baseline. The acute event in these patients was more often unstable angina pectoris and less commonly Q-wave myocardial infarction. With coronary angiography, patients with prior EVD more often had multivessel disease. During the 10 months of follow-up, the presence of EVD was predictive of an increased hazard of death, reinfarction, recurrent ischemia, stroke, and a composite of these events. Despite the increased severity of the CAD and increased risk of events, patients with EVD were treated less frequently with β-blockers and more frequently with calcium blockers. Despite patients with EVD having a 45% higher incidence of hypercholesterolemia, lipid-lowering agents were prescribed in a similar percentage of patients as patients without EVD. Conclusion In patients with acute coronary syndromes, the presence of prior CVA, TIA, or PAD is associated with more extensive CAD and worse outcome. These patients appear to receive less aggressive treatment, which may explain, at least in part, their worse outcome. (Am Heart J 2003;145:622-7.)