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Although depression is a risk factor for stroke in large prospective studies, it is unknown whether these conditions have a shared genetic basis.We applied a polygenic risk score (PRS) for major depressive disorder derived from European ancestry analyses by the Psychiatric Genomics Consortium to a genome-wide association study of ischemic stroke in the Stroke Genetics Network of National Institute of Neurological Disorders and Stroke. Included in separate analyses were 12 577 stroke cases and 25 643 controls of European ancestry and 1353 cases and 2383 controls of African ancestry. We examined the association between depression PRS and ischemic stroke overall and with pathogenic subtypes using logistic regression analyses.The depression PRS was associated with higher risk of ischemic stroke overall in both European (P=0.025) and African ancestry (P=0.011) samples from the Stroke Genetics Network. Ischemic stroke risk increased by 3.0% (odds ratio, 1.03; 95% confidence interval, 1.00–1.05) for every 1 SD increase in PRS for those of European ancestry and by 8% (odds ratio, 1.08; 95% confidence interval, 1.04–1.13) for those of African ancestry. Among stroke subtypes, elevated risk of small artery occlusion was observed in both European and African ancestry samples. Depression PRS was also associated with higher risk of cardioembolic stroke in European ancestry and large artery atherosclerosis in African ancestry persons.Higher polygenic risk for major depressive disorder is associated with increased risk of ischemic stroke overall and with small artery occlusion. Additional associations with ischemic stroke subtypes differed by ancestry.