To assess the potential of a single-session multidetector computed tomography (CT) protocol, as compared with established methods, for the etiologic work-up of acute ischemic stroke.\ Patients found to have recently experienced an ischemic stroke were recruited for this prospective study after institutional review board approval was obtained. Each patient was scheduled for two evaluation strategies: (a) a standard approach involving transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE), duplex ultrasonography (US) of the neck vessels, and magnetic resonance (MR) angiography of the neck and brain vessels; and (b) a protocol involving single-session multidetector CT of the heart, neck, and brain vessels. The authors sought to determine the major etiologic factors of stroke, including cardiac sources of embolism and atheroma of the aortic arch and the extra- and intracranial vessels, by using both strategies.\ Multidetector CT, MR imaging, and duplex US were performed in 46 patients, 39 of whom also underwent TEE. The sensitivity and specificity of multidetector CT were 72% (18 of 25 cases) and 95% (20 of 21 cases), respectively, for detection of cardiac sources and 100% (24 of 24 cases) and 91% (20 of 22 cases), respectively, for detection of major arterial atheroma. For the 46 cases of stroke, the final etiologic classifications determined by using the standard combination approach were cardiac sources in 20 (44%) cases, major arterial atheroma in nine (20%), multiple sources in four (9%), and cryptogenic sources in 13 (28%). Multidetector CT facilitated correct etiologic classification for 38 (83%) of the 46 patients.\ Multidetector CT is a promising tool for etiologic assessment of ischemic stroke, although the identification of minor cardiac sources with this examination requires the establishment of robust criteria.