Background Only a very few studies had compared the differences in topographic patterns of cerebral infarcts between middle cerebral artery (MCA) and internal carotid artery (ICA) disease. Besides, the comparison of clinical features and outcomes between MCA and ICA disease had rarely been reported. Objectives To compare the clinical, imaging features and outcome of MCA versus ICA disease. Methods We prospectively enrolled 1172 patients with noncardiogenic ischemic stroke in ipsilateral ICA or MCA territory. Clinical, neuroradiologic and outcome of the two groups were compared in this observational cohort study. Results The ICA group more frequently presented with decreased alertness, gaze palsy, aphasia, and neglect than the MCA group at admission, and more often had higher National Institute of Health stroke scale score at admission and discharge. Meanwhile, the ICA group more frequently had multiple acute infarcts, watershed infarcts, territorial infarct, small cortical infarct, and responsible artery stenosis 70%. Whereas penetrating artery infarct and parent artery occluding penetrating artery was more often associated with MCA disease. The ICA group more frequently had inhospital complications of pneumonia and deep vein thrombosis, more often had disability at discharge, and had more recurrent ischemic stroke or transient ischemic attack in 1 Year. Multivariable logistic regression identified male (OR, 1.99; 95% CI, 1.30 to 3.05; P = 0.002), history of coronary heart disease (OR, 1.85; 95% CI, 1.03 to 3.32; P = 0.041), multiple acute infarcts (OR, 4.18; 95% CI, 2.07 to 8.45; P<0.0001), and territorial infarct (OR, 2.23; 95% CI, 1.52 to 3.27; P<0.0001) was more often associated with ICA territory disease. Conclusions The clinical, radiologic characteristics and outcome are distinctively different between ICA and MCA disease. Compared to MCA disease, ICA disease has more serious clinical and radiologic manifestation, and poorer outcome. Copyright: © 2019 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.