OBJECTIVE To determine the cause of pulmonary hypertension (PH) in systemic sclerosis (SSc) patients since PH can occur because of pulmonary arteriopathy, pulmonary parenchymal destruction, and left ventricular cardiac dysfunction. METHODS Consecutive case series in a university hospital. METHODS Nine SSc patients with PH (mean pulmonary artery pressure, 41 mm Hg), with (n = 6) or without (n = 3) concomitant interstitial lung disease (ILD). METHODS Acute infusion of epoprostenol was begun at 2 ng/kg/min and was titrated upward at a rate of 2 ng/kg/min every 30 min until symptomatic complications developed or pulmonary artery vascular resistance (PVR) was reduced by 50%. RESULTS Eight of nine patients demonstrated a reduction of > or = 20% in PVR, suggesting that vasoreactivity is common despite the presence of significant ILD. A single patient had no response to infusion with unchanged hemodynamics and oxygenation. One patient developed hypoxemia as cardiac output increased, suggesting a worsening of ventilation/perfusion matching or the presence of an anatomic shunt. Acute pulmonary edema developed in one patient at an infusion rate of 6 ng/kg/min. The results of cardiac catheterization suggested that pulmonary edema was caused by SSc heart disease. CONCLUSIONS SSc patients with ILD have diverse and sometimes multiple causes of PH that can be determined by short-term epoprostenol infusion. Beneficial effects can be obtained from epoprostenol despite extensive ILD.