OBJECTIVE To determine the effects of short-term, maximum-tolerated-dose and long-term, optimum-dose iloprost treatment of severe pulmonary hypertension associated with systemic sclerosis (SSc) and the primary antiphospholipid syndrome (APS). METHODS Three patients with SSc and 2 with APS who had failed to respond to oral vasodilator therapy for pulmonary hypertension were enrolled in a 32-week, open, prospective trial. Short-term infusion of maximum-tolerated doses and continuous infusion of optimum doses of iloprost were carried out following baseline cardiac catheterization. Catheterization was repeated at 2 and 32 weeks. All 5 patients completed the study and continued therapy for an average of 82 weeks (range 58-103). RESULTS Acute infusion of maximum tolerated doses significantly ameliorated the cardiac index (0.92 liters/minute/m2; P < 0.01), pulmonary artery O2 saturation (10.6%; P < 0.05), and pulmonary resistance (-6.7 units; P < 0.05). After 2 weeks of continuous infusion of optimum doses, there was improvement in pulmonary resistance (> or = 16%) and pulmonary artery O2 saturation (> 30%) in the 2 patients with primary APS. After 2 and 32 weeks, the 3 SSc patients showed variable hemodynamic responses. New York Heart Association functional class and exercise tolerance improved in all patients. There was 1 episode of bacteremia, and 1 patient died after 72 weeks of study. CONCLUSIONS Continuous iloprost infusion may improve exercise tolerance and quality of life in patients with severe pulmonary hypertension associated with SSc and primary APS.