PURPOSE: We evaluated whether combined diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) could identify stroke subtypes in patients with acute small subcortical infarcts (SSI), according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classifications. MATERIALS AND METHODS: A total of 182 patients with acute SSI in the middle cerebral artery territory were studied retrospectively. Lesions on DWI were evaluated as number, location, and combined cortical spotty lesion. PWI using mean transit time (MTT) was classified as type 1 (normal perfusion), type 2 (matched perfusion-diffusion), and type 3 (mismatched perfusion-diffusion). RESULTS: There were 126 (69.2%) patients with small vessel disease, 46 (25.3%) with large artery atherosclerosis, and 10 (5.5%) with cardio-embolism in patients with acute SSI within the middle cerebral artery territory. We found a significant overall association of DWI and PWI lesion patterns and classification with stroke subtype by using the TOAST criteria (p < .05). Multiple unilateral lesions, accompanying cortical embolic signals and type 3 pattern of perfusion abnormality were associated significantly with large-artery atherosclerosis. CONCLUSION: The most common pathogenesis of SSI was small vessel disease. Our study indicates that multiple unilateral SSI or cortical embolic signals accompanying mismatched perfusion-diffusion warrant evaluation of the presence of large artery disease.