Background Natriuretic peptides have prognostic value across a wide spectrum of cardiovascular diseases and may predict cognitive dysfunction in patients with cardiovascular disease, even in the absence of previous stroke. Little is known about the association of natriuretic peptides with cognitive function in community-dwelling adults. We assessed the association between N-terminal pro B-type natriuretic peptide (NT-proBNP) levels and cognitive function in community-dwelling ambulatory older adults in the Rancho Bernardo Study. Methods We studied 950 men and women, aged 60 years and older, who attended a research clinic visit where a medical history and examination were performed, and blood for cardiovascular disease risk factors and NT-proBNP levels were obtained. Three cognitive function tests were administered: the Mini Mental State Examination (MMSE), Trail-Making Test B (Trails B), and Category Fluency. Results Participants with high NT-proBNP levels (≥450 pg/mL; n=198) were older and had a higher prevalence of coronary heart disease (12% vs 30%), and stroke (5% vs 11%; P ≤.001 for both). In unadjusted analyses, all 3 cognitive function test scores were significantly associated with NT-proBNP levels (P <.001). After adjusting for age, sex, education, hypertension, body mass index, exercise, alcohol use, smoking, low density lipoprotein cholesterol, creatinine clearance, and previous cardiovascular disease, elevated NT-proBNP levels remained independently associated with poor cognitive performance on MMSE (odds ratio [OR] 2.0; 95% confidence interval [CI], 1.1-3.6; P =.02) and Trails B (OR 1.7; 95% CI, 1.2-2.7; P =.01), but not Category Fluency (OR 1.4; 95% CI, 0.9-2.2; P =.19). Results were unchanged after excluding the 6% of participants with a history of stroke. Conclusions NT-proBNP levels were strongly and independently associated with poor cognitive function in community-dwelling older adults.