Background: Improved understanding of the etiology of cognitive impairment is needed to develop effective preventive interventions. Higher amino-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biomarker of cardiac dysfunction associated with risk of cardiovascular diseases and stroke in apparently healthy people. Objective: To study the association of NT-proBNP with risk of incident cognitive impairment. Methods: The Reasons for Geographic and Racial Differences in Stroke is a national cohort study of 30,239 black and white Americans age 45 and older at baseline, enrolled in 2003-7. Among participants without prebaseline stroke or cognitive impairment, baseline NT-proBNP was measured in 470 cases of incident cognitive impairment and 557 controls. Cases were participants scoring below the 6th percentile of demographically-adjusted means on at least 2 of 3 serially administered tests (word list learning, word list recall and semantic fluency) over 3.5 years follow-up. Results: Adjusting for age, gender, race, region of residence, education, and income, there was an increased odds ratio of incident cognitive impairment with increasing NT-proBNP; participants in the 4th versus 1st quartile (>127 versus ≤33 pg/ml) had a 1.69-fold increased odds (95 CI 1.11-2.58). Adjustment for cardiovascular risk factors and presence of an apolipoprotein E4 allele had no substantial impact on the odds ratio. Results did not differ by age, race, gender, or presence of an apolipoprotein E4 allele. Conclusion: Higher NT-pro-BNP was associated with incident cognitive impairment in this prospective study, independent of atherogenic and Alzheimer's disease risk factors. Future work should clarify pathophysiologic connections of NT-proBNP and cognitive dysfunction.