The cost-effectiveness of N-terminal pro-brain natriuretic peptide (NT-pro-BNP) in dyspneic patients in emergency departments (EDs) is unknown. The objective of this study was to assess the cost-effectiveness of NT-pro-BNP testing for the evaluation and initial management of patients with dyspnea in the ED setting. A decision model was developed to evaluate the cost-effectiveness of diagnostic assessment and patient management guided by NT-pro-BNP, compared with standard clinical assessment. The model includes the diagnostic accuracy of the 2 strategies for congestive heart failure and resulting events at 60-day follow-up. Clinical data were obtained from a prospective blinded study of 599 patients presenting to the ED with dyspnea. Costs were based on the Massachusetts General Hospital cost accounting database. The model predicted serious adverse events during follow-up (i.e., urgent care visits, repeat ED presentations, rehospitalizations) and direct medical costs for echocardiograms and hospitalizations. NT-pro-BNP-guided assessment was associated with a 1.6% relative reduction of serious adverse event risk and a 9.4% reduction in costs, translating into savings of $474 per patient, compared with standard clinical assessment. In a sensitivity analysis considering mortality, NT-pro-BNP testing was associated with a 1.0% relative reduction in post-discharge mortality. The optimal use of NT-pro-BNP guidance could reduce the use of echocardiography by up to 58%, prevent 13% of initial hospitalizations, and reduce hospital days by 12%. In conclusion, on the basis of this model, the use of NT-pro-BNP in the diagnostic assessment and subsequent management of patients with dyspnea in the ED setting could lead to improved patient care while providing substantial cost savings to the health care system.