In developing countries, rheumatic valve disease (RVD) is still prevelant. Management of RVD depends on symptomatology, physical examination and echocardiographic evaluation, all of which, however, might be inadequate. Reliable biomarkers to establish severity of RVD and predict complications would be highly beneficial. Urotensin II is regarded as a cardiovascular autacoid/hormone, and its role in cardiovascular diseases is emerging. We hypothesized urotensin II might have pathophysiological roles in RVD. We investidated 71 patients with RVD (mean age 40 ± 12 years, 17 female patients) and 25 normal subjects (mean age 40 ± 7 years, 8 female patients). We assessed their New York Heart Association (NYHA) functional class, RVD severity and pulmonary artery pressure (PAP), and measured plasma urotensin II levels. Mitral regurgitation (r = 0.226, p = 0.02), tricuspid regurgitation (r = 0.238, p = 0.02), PAP (r = 0.320, p = 0.01), and NYHA class (r = 0.213, p = 0.03) correlated positively with urotensin II levels. There was positive correlation between urotensin II levels and severity of mitral regurgitation (r = 0.248, p = 0.01) and tricuspid regurgitation (r = 0.326, p = 0.001). In linear regression analysis, only PAP was predictive of urotensin II (β = 0.3; p = 0.02). In conclusion, this is the first study showing that plasma urotensin II is elevated in chronic RVD, associated with severe mitral and tricuspid valve regurgitation. Furthermore, urotensin II level is correlated with NYHA functional class, and the increase in PAP is predictive of plasma urotensin II.