N-terminal prohormone B-type natriuretic peptide (NT-proBNP) is an important biomarker of prognosis in heart failure and single valve disease. There are limited studies of complex valve disease. Patients with complex valve disease adopt a sedentary lifestyle, so symptoms may be difficult to detect. The authors aimed to determine whether NT-proBNP correlates with the severity of the valve lesion and underlying cardiac function and whether resting NT-proBNP predicts impaired peak VO2 in patients with complex valve disease. Forty-five patients with complex moderate to severe stenosis or regurgitation of the heart valves underwent a clinical assessment, echocardiography, resting NT-proBNP assessment, and formal cardiopulmonary exercise testing. In a multivariate analysis, the log NT-proBNP (β=-9.3, SE=1.9, P<0001) and lean body weight (β=0.59, SE=0.22, P=01) were dominant independent predictors of peak VO2. An NT-proBNP value of 84 pmol/L had 77% sensitivity and 70% specificity to predict impaired functional capacity, peak VO2 <60% (predicted), area under the curve=0.80. Resting NT-proBNP was the best predictor of peak VO2 in patients with complex valve disease, while symptoms and ejection fraction are a less reliable guide.