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To determine if depression, cognitive impairment without dementia (CIND), and/or dementia are each independently associated with risk of ischemic stroke and to identify characteristics that could modify these associations.This retrospective-cohort study examined a population-based sample of 7031 Americans older than 50 years participating in the Health and Retirement Study (1998–2008) who consented to have their interviews linked to their Medicare claims. The eight-item Center for Epidemiologic Studies Depression Scale and/or International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) depression diagnoses were used to identify baseline depression. The Modified Telephone Interview for Cognitive Status and/or ICD-9-CM dementia diagnoses were used to identify baseline CIND or dementia. Hospitalizations for ischemic stroke were identified via ICD-9-CM diagnoses.After adjusting for demographics, medical comorbidities, and health-risk behaviors, CIND alone (odds ratio [OR] = 1.37, 95% confidence interval [CI] = 1.11–1.69) and co-occurring depression and CIND (OR = 1.65, 95% CI = 1.24–2.18) were independently associated with increased odds of ischemic stroke. Depression alone was not associated with odds of ischemic stroke (OR = 1.11, 95% CI = 0.88–1.40) in unadjusted analyses. Neither dementia alone (OR = 1.09, 95% CI = 0.82–1.45) nor co-occurring depression and dementia (OR = 1.25, 95% CI = 0.89–1.76) were associated with odds of ischemic stroke after adjusting for demographics.CIND and co-occurring depression and CIND are independently associated with increased risk of ischemic stroke. Individuals with co-occurring depression and CIND represent a high-risk group that may benefit from targeted interventions to prevent stroke.