Plasma levels of N-terminal pro-brain natriuretic peptide (NT-pro-BNP) are elevated in severe mitral regurgitation, but their relation to functional capacity and cardiac remodeling is not well defined. We evaluated the role of NT-pro-BNP as a marker of functional capacity, symptoms, and cardiac remodeling in 38 patients with severe degenerative mitral regurgitation and preserved left ventricular ejection fraction. The NT-pro-BNP levels increased progressively with New York Heart Association (NYHA) functional class: NYHA class I (geometric mean [GM] 97.1 pg/ml), NYHA class II (GM 169.8 pg/ml), and NYHA III (GM 457.6 pg/ml; p = 0.015). The end-systolic volume index (r = 0.52, p = 0.001), end-diastolic volume index (r = 0.46, p = 0.003), left atrial volume index (r = 0.4, p = 0.01), regurgitant volume index (r = 0.38, p = 0.02), regurgitant fraction (r = 0.46, p = 0.003), and end-diastolic sphericity index (r = 0.56, p <0.001) all correlated significantly with NT-pro-BNP. The NT-pro-BNP levels correlated significantly with the exercise parameters: maximum oxygen uptake (r = -0.6, p <0.001), exercise time (r = -0.52, p <0.001), and oxygen pulse (r = -0.57, p <0.001). In contrast, only weak correlations were obtained between the exercise and echocardiographic variables. NT-pro-BNP was a strong independent predictor of maximum oxygen uptake (p = 0.001). In conclusion, the results of this study have demonstrated that NT-pro-BNP increases progressively with worsening symptoms, is linked to the extent of LV remodeling, and is an independent predictor of functional capacity. NT-pro-BNP may have a role in the optimal treatment of patients with severe mitral regurgitation.