Although patients with COPD often have elevated pulmonary artery pressures (PAP) and pulmonary vascular resistance (PVR), it is uncertain whether treatment of this pulmonary hypertension is beneficial. We evaluated the extent of pulmonary hypertension in 16 patients with severe COPD complicated by acute respiratory failure and pulmonaryhypertension. We assessed the hypothesis that the vasodilator prostacyclin (PGI2) would reduce PVR and improve systemic O2 transport. Patients with a COPD exacerbation requiring mechanical ventilation, and mean PAP greater than 30 mm Hg, were randomized to receive PGI2 or placebo, in addition to conventional therapy. Randomization to PGI2 or placebo therapy occurred 1 to 12 h after intubation, while the patient was mechanically ventilated. An optimal PGI2 dose (2 to 12 ng/kg/min, IV) was established in an initial dose-ranging study and then this dose was infused continuously for 48 h. PGI2 initially reduced PVR, but this effect dissipated within 24 h, indicating the development of tachyphylaxis. Tolerance to the adverse effects of PGI2 (tachycardia, hypotension, flushing, and headache) also developed over time. PGI2 treatment was associated with a significant fall in PaO2 but no increase in systemic oxygen transport. PGI2 proved to be a non-selective vasodilator that caused mild hypoxemia. Despite acute respiratory failure, pulmonary hypertension is mild in patients with severe COPD receiving mechanical ventilation and IV PGI2 is not beneficial in such patients.