OBJECTIVES: To evaluate the cost-effectiveness of N-terminal pro-Brain natriuretic peptide (NT-proBNP) in the diagnostic assessment of patients with dyspnea in the Emergency Department (ED). METHODS: We developed a decision model to compare standard clinical assessment versus patient evaluation guided by NT-proBNP (Elecsys proBNP assay, Roche Diagnostics). The model represents diagnostic accuracy for acute congestive heart failure (CHF) of both strategies and resulting events during the initial ED visit and 60-day follow-up. Clinical data were based on the PRIDE Study. In this prospective study of 599 patients presenting to the ED with dyspnea, an NT-proBNP>900 pg/ml was the strongest predictor of final diagnosis of acute CHF, as judged by blinded physicians. The primary clinical endpoint of our cost-effectiveness analysis was serious adverse events (SAE) including urgent care visits, ED presentations, hospitalizations, and deaths. Secondary endpoints were accuracy of CHF diagnosis and 60-day mortality. Our model assumes that resource utilization depends on true CHF status and probability of CHF as estimated by ED physicians, thus, the economic endpoint was reduction in direct medical costs due to saved echocardiograms and hospitalizations. Costs were based on the MGH cost accounting database, Transition Systems Inc. (TSI). RESULTS: Diagnostic assessment and management with NT-proBNP was associated with a 10% reduction in direct medical costs, a cost savings of $492 per patient, and a 2.5% relative risk reduction of SAE. NT-proBNP testing dominated standard assessment. Furthermore, NT-proBNP testing was associated with a 1.2% reduction in 60-day mortality, in spite of a 1% reduction in overall diagnostic accuracy. NT-proBNP testing reduced echocardiograms by 58%, prevented 13% of initial hospitalizations and reduced hospital days by 12%. CONCLUSIONS: The use of NT-proBNP in the diagnostic assessment of acute CHF improves patient outcomes and leads to potential cost-savings of more than $500 million in the US health care system.