BACKGROUND The sympathetic nervous system has been reported to be activated in pulmonary arterial hypertension (PAH). OBJECTIVE We investigated the prognostic significance of muscle sympathetic nervous system activity (MSNA) in PAH. METHODS Thirty-two patients with PAH were included in the study and underwent a measurement of MSNA over a 6-year period of time. They had undergone a concomitant evaluation of New York Heart Association (NYHA) functional class, a 6-minute walk distance (6MWD), an echocardiographic examination, and a right heart catheterization for diagnostic or reevaluation purposes. The median follow-up time was 20.6 months (interquartile range, 45.8 mo). Clinical deterioration was defined by listing for transplantation or death. RESULTS Seventeen patients presented with clinical deterioration. As compared with the 15 others, they had an increased MSNA (80 +/- 12 vs. 52 +/- 18 bursts/min; P < 0.001) and heart rate (88 +/- 17 vs. 74 +/- 12 bpm; P = 0.01), a lower 6MWD (324 +/- 119 vs. 434 +/- 88 m; P < 0.01) and a deteriorated NYHA functional class (3.6 +/- 0.5 vs. 2.9 +/- 0.8; P < 0.001). The hemodynamic variables were not different. MSNA was directly related to heart rate and inversely to 6MWD. A univariate analysis revealed that increased MSNA and heart rate, NYHA class IV, lower 6MWD, and pericardial effusion were associated with subsequent clinical deterioration. A multivariate analysis showed that MSNA was an independent predictor of clinical deterioration. For every increase of 1 burst/minute, the risk of clinical deterioration during follow-up increased by 6%. CONCLUSIONS Sympathetic nervous system activation is an independent predictor of clinical deterioration in pulmonary arterial hypertension.