Background and Purpose: Improved identification of those at risk of stroke might improve prevention. We evaluated the association of the cardiac function biomarker N-terminal pro-B-type natriuretic peptide (NT-proBNP) with stroke risk in the 30 239 black and white participants of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. METHODS-: During 5.4 years of follow-up after enrollment in 2003 to 2007, NT-proBNP was measured in baseline blood samples of 546 subjects with incident ischemic stroke and 956 without stroke. RESULTS-: NT-proBNP was higher with older age and in those with heart disease, kidney disease, atrial fibrillation, and lower low-density lipoprotein-cholesterol. Adjusting for age, race, sex, income, education, and traditional stroke risk factors, there was an increased risk of stroke across quartiles of NT-proBNP; participants with NT-proBNP in the top versus the bottom quartile had a hazard ratio of 2.9 (95% confidence interval, 1.9-4.5). There was no impact of added adjustment for kidney function and heart failure. Among pathogenetic stroke subtypes, the association was largest for cardioembolic stroke, with a hazard ratio of 9.1 (95% confidence interval, 2.9-29.2). Associations did not differ by age, sex, or race, or after excluding those with baseline heart failure or atrial fibrillation. Predicted stroke risk was more accurate in 27% of participants if NT-proBNP was considered after traditional stroke risk factors (P<0.001). CONCLUSIONS-: NT-proBNP was a major independent risk marker for stroke. Considering this and other data for stroke, coronary disease, and atrial fibrillation, the clinical use of NT-proBNP measurement in primary prevention settings should be considered. © 2014 American Heart Association, Inc.