This multicenter, open-label study provides the first assessment of the safety and acute nemodynamic effects of a short-term infusion of 15AU81, a chemically stable analog of prostacyclin, in patients with New York Heart Association class III or IV heart failure. Twelve patients underwent sequential dose escalation by increasing the rate of the infusion at 15-minute intervals until the drug was no longer tolerated. Patients then received a 90-minute infusion at their maximum tolerated dose. The infusion was then discontinued and the subjects were observed during a 90-minute washout segment. Serial hemodynamic measurements were made throughout the dose-ranging, maintenance, and washout segments. A significant decrease in systemic vascular resistance (1,935 ± 774 vs 1,243 ± 351 dynes·s·cm-5; p < 0.001) and pulmonary vascular resistance (395 ± 335 vs 223 ± 198 dynes·s·cm-5; p = 0.008) occurred from the infusion of vehicle to the maximum tolerated dose. During dose titration, there was a a significant increase in cardiac index (1.9 ± 0.7 vs 2.6 ± 0.6 liters/min/m2; p <0.001) and a tendency for a mild reduction in pulmonary artery wedge pressure (18 ± 7 vs 17 ± 6; p = 0.055) for the 8 patients with values on vehicle and maximum tolerated dose. These hemodynamic changes persisted during the maintenance infusion and disappeared rapidly during the washout segment. The most common adverse event to limit dose-ranging was headache, which occurred at a mean maximum tolerated dose of 36 ± 15 ng/kg/min. Administration of 15AU81 was associated with significant acute hemodynamic improvement in patients with severe heart failure. The stable chemical nature of this compound may permit effective administration by nonparenteral routes.