Objectives: This study was designed to assess the tolerability and efficacy of the oral endothelin receptor antagonist bosentan in adult patients with pulmonary arterial hypertension (PAH) related to congenital heart disease (CHD). Background: Severe PAH in the setting of CHD is a debilitating syndrome for which there are limited treatment options. This is the first long-term study experience in adults reporting on the tolerability and efficacy of therapy with bosentan for this patient population. Methods: A 12-month single-center experience with 19 women and 5 men with PAH associated with CHD (79% in New York Heart Association [NYHA] class III) was analyzed. Hemodynamic responses, exercise capacity, and Borg dyspnea index were assessed prior to the administration of bosentan, and again at 3, 6, and 12 months after the study began. Clinical assessments were performed monthly for up to 12 months. The change from baseline was tested using the Wilcoxon pairs test. Results: There was significant improvement in hemodynamics from baseline to 12 months (mean [± SD] systolic pulmonary arterial pressure, 99 ± 30 to 87 ± 28 mm Hg [p ≤ 0.001]; mean pulmonary arterial pressure, 60 ± 18 to 52 ± 17 mm Hg [p ≤ 0.001]; mean right atrial pressure, 12 ± 6 to 8 ± 5 mm Hg [p ≤ 0.001]; mean pulmonary vascular resistance, 663 ± 386 to 504 ± 307 dyne · s · cm-5 [p < 0.01]; pulmonary capillary wedge pressure, 15 ± 5 to 11 ± 3 mm Hg [p < 0.001]). NYHA functional class also improved from baseline to 12 months (NYHA class I/II range, 17 to 71%; p < 0.001). There was a marginally significant trend toward improvement in the mean 6-min walk test distance at 12 months (299 ± 85 to 330 ± 95 m; p = 0.05). Three patients needed to discontinue bosentan therapy because of elevated liver function test results. There were no deaths or hospitalizations, and no significant change in arterial oxygen saturation had occurred at 12 months. Conclusions: Bosentan therapy improved hemodynamics and NYHA class in patients with PAH that was associated with CHD. These effects were seen after 3 to 6 months. Bosentan therapy may provide an effective alternative to current therapies in this patient population.