In nine patients with severe pulmonary arterial hypertension (one primary and the others secondary to systemic sclerosis or pulmonary embolism), ventilation/perfusion (V̇/Q̇) ratios were measured during right-heart catheterization using a multiple inert gas elimination technique. V̇/Q̇ ratios were assessed before and after administration of IV epoprostanol, 8.5 ± 1.8 ng/kg/min. Following 5.1 ± 1.5 months of inhaled iloprost therapy (20 μg tid), V̇/Q̇ ratios were again measured before and 15 min after inhalation of 20 μg of iloprost. Before treatment, mean (± SD) pulmonary artery pressure was 46.2 ± 13.5 mm Hg. Pulmonary vascular resistance (PVR) was 8.61 ± 4.52 mm Hg/L/min, and cardiac output was 4.22 ± 0.75 L/min. There was a moderately elevated shunt of 5.1% (range, 1.6 to 19.5%) of cardiac output and substantial high V̇/Q̇ ventilation of 8.1% of minute ventilation (range, 2.9 to 36.8%), and increased dispersion of perfusion and ventilation for the V̇/Q̇ ratios (SD of the distribution of perfusion [log SDQ], 0.93 ± 0.31; and SD of the distribution of ventilation, 08 ± 0.23). Epoprostanol infusion resulted in a 21 ± 18% reduction in PVR and a 36 ± 14% reduction in systemic vascular resistance. log SDQ was further increased by 30 ± 33%. The mean increase in shunt was approximately 60% higher during epoprostanol than after iloprost (p = 0.06). However, due to increased cardiac output and raised venous oxygen saturation (Svo2), Pao2 was not significantly altered.