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Objective This study was performed to determine whether a dual-biomarker approach using N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and galectin-3 optimizes the diagnosis and risk stratification of acute cardiac dyspnea. Atypical clinical manifestations and overlapping pathologies require objective and effective diagnostic methods to avoid treatment delays.Methods This prospective observational study included 208 patients who presented to the emergency department for acute dyspnea. NT-proBNP and galectin-3 were measured upon admission. The patients were divided into two groups according to the etiology of their clinical manifestations: cardiac and non-cardiac dyspnea. The patients’ New York Heart Association functional class, left ventricular ejection fraction, and discharge status were assessed.Results Diagnostic criteria for acute heart failure were fulfilled in 61.1% of the patients. NT-proBNP and galectin-3 were strongly and significantly correlated. Receiver operating characteristic analysis revealed similar areas under the curve for both markers in the entire group of patients as well as in the high-risk subsets of patients.Conclusions The diagnostic performance of NT-proBNP and galectin-3 is comparable for both the total population and high-risk subsets. Galectin-3 adds diagnostic value to the conventional NT-proBNP in patients with acute cardiac dyspnea, and its utility is of major interest in uncertain clinical situations.