Background and Purpose-Single subcortical infarction (SSI) may be classified as proximal SSI (pSSI) or distal SSI (dSSI) according to its location within the middle cerebral artery territory. Few studies have examined the differences in clinical outcome between the two. Our study investigated such differences in patients with pSSI or dSSI and examined their baseline characteristics and indicators for small-vessel disease. Methods-We prospectively enrolled 400 patients with SSI (208 pSSI and 192 dSSI) who had no middle cerebral artery disease on MR angiography. Data compared included clinical information, lesion size, prevalence of lacune and leukoaraiosis at baseline, National Institutes of Health Stroke Scale score and modified Rankin Scale score at discharge, and any deterioration during admission or recurrence of ischemic stroke <1 year. Results-In multivariable logistic regression analysis, dSSI was independently associated with patient's history of stroke, admission National Institutes of Health Stroke Scale score <= 3, Fazekas score >= 3, presence of lacune, but not hyperlipidemia. Patients with dSSI had shorter length of hospital stay, lower rate of functional dependence at discharge (modified Rankin Scale score >= 2), and lower deterioration or recurrence risk of ischemic stroke in 1 year. Multivariable logistic regression analysis showed that factors associated with higher deterioration or recurrence risk of ischemic stroke at 1 year included female sex, history of coronary heart disease, pSSI, and not on antithrombotics <48 hours of admission. Conclusions-Compared with pSSI, patients with dSSI likely had small-vessel diseases but better clinical outcome.