Background: Differentiation between acute cortical and subcortical ischemic stroke may be problematic when cortical stroke presents without obvious cortical deficits such as aphasia, neglect or hemianopia. This study explores stroke risk factors and clinical variables that may assist in this differentiation. Methods: Records of consecutive patients with acute ischemic stroke, examined within 72 h of symptom onset, were reviewed. Stroke type was verified by clinical course and follow-up imaging. Stroke risk factors and acute examination findings were compared by odds ratios and positive predictive values for cortical and subcortical stroke. Results: For 355 patients studied, 237 had cortical stroke and 118 had subcortical stroke. Odds ratios for cortical stroke were highest for atrial fibrillation by EKG (OR = 4.77, CI = 2.08–10.94), recent hospitalization (OR = 4.51, CI = 2.39–8.53) and nonalert mental status (OR = 4.50, CI = 2.29–8.87). Possible cardioembolic condition, ischemic heart disease and peripheral vascular disease were also significant, but hypertension, age and diabetes mellitus were not significantly different for the stroke subtypes. Cortical deficits were absent in 19.4% of cortical stroke patients on initial examination. Predictive models were generated based on the presence or absence of cortical deficits and the interaction of significant risk factors with degree of motor deficit. Conclusions: There are clinical features that, in addition to initial examination, may help differentiate cortical from subcortical ischemic stroke. These features may be relevant to both diagnostic and therapeutic approaches to acute stroke.