Poststroke cognitive impairment is a debilitating consequence of stroke. The aim of this study was to assess whether Actovegin confers cognitive benefit in patients who have had an ischemic stroke. This was a 12-month, parallel-group, randomized, multicenter, double-blind, placebo-controlled study. Eligible patients were ≥60 years of age with a Montreal Cognitive Assessment test score of ≤25 points. Patients were randomized into 2 groups within 1 week of acute supratentorial ischemic stroke in a 1:1 ratio: Actovegin (a deproteinized hemoderivative of calf blood, 2000 mg/d for ≤20 intravenous infusions followed by 1200 mg/d orally) or placebo for 6 months. Patients were treated in accordance with standard clinical practice for a further 6 months. The primary end point was the change from baseline in Alzheimer's Disease Assessment Scale, cognitive subscale, extended version at 6 months. Two-hundred forty-eight patients were randomized to Actovegin and 255 patients to placebo. At month 6, the least squares mean change from baseline in Alzheimer's Disease Assessment Scale, cognitive subscale, extended version was -6.8 for Actovegin and -4.6 for placebo; the estimated treatment difference was -2.3 (95% confidence interval, -3.9, -0.7; =0.005). Recurrent ischemic stroke was the most frequently reported serious adverse event, with a nonsignificantly higher number for Actovegin versus placebo. Actovegin had a beneficial effect on cognitive outcomes in patients with poststroke cognitive impairment. The safety experience was consistent with the known safety and tolerability profile of the drug. These results warrant confirmation in additional robustly designed studies. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01582854.