Cerebral microinfarcts (CMI) are associated with intracerebral hemorrhage due to small vessel disease (SVD) in studies not including an ischemic etiologic workup. We aimed to determine their incidence and potential causes in a large ischemic stroke (IS) cohort.Consecutive patients with MRI-confirmed IS within 72 hours of onset were enrolled. Subjects had either single high-risk embolic source (cardioembolic or large vessel disease) or no embolic source. CMIs were classified by their relationship to the primary infarct as within or outside the same vascular territory. White matter hyperintensities (WMH) and microbleeds were markers SVD severity. Multivariable regression tested the association between CMIs and potential etiologies.We analyzed 946 IS patients, mean age 69 ± 15 years, 46% female. We detected CMI (≤5 mm) on diffusion-weighted imaging in 269 (28%) subjects, 190 (71%) within the vascular territory of the primary infarct. Large-vessel atherosclerosis (P.001), cardioembolic source (P.001), higher WMH (P = .032) and lower systolic blood pressure (SBP, P = .024) were independently associated with the presence of CMI. While SBP was associated with CMI in any location (P.05), WMH was only associated with CMI outside the territory of the primary infarct (P = .033), and large vessel atherosclerosis with CMI within the primary infarct territory (P = .004).CMIs occurring within the vascular territory of a larger infarct are more likely embolic, but those occurring outside are probably related to SVD. Our findings suggest a role for SVD in pathogenesis of CMIs and emphasize the importance of etiologic workup to identify alternate etiologies.