Epoprostenol therapy has improved survival in primary pulmonary hypertension; however, only two thirds of patients are alive 3 years after starting treatment. Combined therapy with sildenafil, a phosphodiesterase 5 inhibitor, may provide additional benefit. The authors prospectively evaluated the acute hemodynamic and biochemical effects of sildenafil and inhaled nitric oxide, alone and in combination, in 8 patients with primary pulmonary hypertension receiving chronic epoprostenol. Average duration of epoprostenol therapy was 2.9 +/- 1.6 years (mean +/- SD) and mean dose was 25.7 +/- 10.8 ng/kg/min. A single 50 mg dose of sildenafil decreased mean pulmonary arterial pressure 10% (P<.05), increased cardiac output 8%, and decreased pulmonary vascular resistance 24% (P<.005). Although nitric oxide led to a similar decrease in mean pulmonary arterial pressure of 10% (P<.05), cardiac output was unchanged, resulting in a decrease in pulmonary vascular resistance of only 13%, which was not statistically different from baseline. These results suggest that sildenafil has greater acute hemodynamic effects than nitric oxide and that it can further reduce pulmonary vascular resistance in patients already demonstrating a benefit from chronic epoprostenol.