Background: Embolic stroke of undetermined source (ESUS) is a recently introduced clinical construct to define non-lacunar cryptogenic ischemic stroke and is the basis for two large international randomized trials recently underway. Diagnostic criteria are a visualized non-lacunar stroke on CT or MRI, absence of atrial fibrillation by history, ECG and at least 24 hours of rhythm monitoring, absence of intracardiac thrombus by echocardiography, no occlusive atherosclerosis based on imaging of the cervical and intracranial arteries, and no specific cause of stroke identified. The frequency and features of ESUS patients have not been characterized previously. Methods: Consecutive patients with recent ischemic stroke were retrospectively reviewed at 20 stroke research centers in 20 different countries to identify those meeting criteria for ESUS, as well as reasons not meeting criteria for the remaining patients. Results: Of 2.090 patients with recent ischemic stroke, 18% met ESUS criteria (range 2% to 36%). Of those not meeting ESUS criteria, major reasons were atrial fibrillation (26%), lacunar stroke (19%), incomplete diagnostic evaluation (18%), carotid artery stenosis >50% (17%), and intracranial stenosis (13%). Excluding those without the required diagnostic evaluation, 22% met criteria for ESUS. Of the 378 ESUS patients, the mean age was 64 years (vs. 68 years for non-ESUS), 56% were men (54% non-ESUS), 16% received tPA, and 33% were taking antiplatelet therapy at stroke onset. Hypertension, diabetes, and coronary artery disease were present in 66%, 26%, and 11%, respectively. At hospital discharge, 93% received antiplatelet therapy, 6% anticoagulant therapy, and 1% no antithrombotic therapy. Conclusions: Ischemic stroke patients meeting criteria for ESUS are not uncommon (22% of ischemic strokes) in stroke centers performing the required diagnostic evaluation. Antiplatelet therapy is overwhelmingly used for secondary prevention in these patients with non-lacunar cryptogenic stroke.