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Objective: To characterize isolated upper extremity (UE) weakness from stroke., Methods: In our Get with the Guidelines-Stroke dataset (n = 7643), 87 patients (1.14%) had isolated UE weakness and underwent thorough stroke evaluation with diffusion-weighted magnetic resonance imaging and good-quality arterial imaging. We analyzed clinical-imaging features, etiology, management, and outcome. Since isolated UE weakness is typically associated with contralateral hand-knob area infarcts, patients were classified into Group-A (motor strip infarct) or Group-B (non-motor strip infarct)., Results: The mean age was 68 years; 66% were male, 72% had hypertension, 22% diabetes, 53% hyperlipidemia, and 16% were smokers. In Group-A (n = 71), 18 patients had single and 53 had multiple infarcts involving the contralateral motor strip. In Group-B (n = 16), 6 patients had contralateral subcortical white matter infarcts, 9 had bihemispheric infarcts and 1 had a brainstem infarct. Compared to Group-B, patients in Group-A more often had carotid artery stenosis or irregular plaque (84.5% versus 50%, P = .006) and large-artery atherosclerosis mechanism (46% versus 19%, P = .05), and less often cardioembolic mechanism (13% versus 44%, P = .008). Among 36 patients with large-artery mechanism, 27 had less than 70% stenosis including 19 with plaque ulceration/thrombus. Recurrent strokes occurred in 10 patients (11.5%), including 5 with mild-moderate carotid stenosis and plaque ulceration/thrombosis, over 1515 days follow-up., Conclusion: Stroke mechanism in acute isolated UE weakness is variable. Contralateral motor-strip infarcts are associated with carotid stenosis, often with plaque ulceration ("vulnerable carotid plaque"), and infarcts in other locations with cardioembolism. Recurrent stroke risk is high especially with mild-moderate carotid artery stenosis and plaque ulceration/thrombus., (Copyright © 2018. Published by Elsevier Inc.)