This study was a prospective, randomized design to compare oxygenation and pulmonary hemodynamics between inhaled nitric oxide (NO) and inhaled prostacylcin (PGI 2), and between inhaled and iv PGI 2 in acute respiratory failure with pulmonary hypertension. Acute respiratory failure with pulmonary hypertension was induced in 12 piglets weighing 9–12 kg by repeated lung lavages and a continuous infusion of the stable endoperoxane analogue of thromboxane. Thereafter the animals were randomly assigned either for NO or PGI 2 application. All animals were treated with different concentrations of NO or different doses of PGI 2 applied iv and inhaled in random order. Continuous monitoring included ECG, central venous pressure (CVP), mean pulmonary artery pressure (MPAP), mean arterial pressure (MAP), artertial oxygen saturation (SaO 2), and mixed venous oxygen saturation (SvO 2) measurements. NO inhalation of 10 ppm resulted in a significant increase in Pao 2/fraction of inspired oxygen (FiO 2) from 7.8±1.34 kPa to 46.1±9.7 kPa. MPAP decreased significantly from 5.1±0.26 kPa to 3.7±0.26 kPa during inhaled NO of 40 ppm; iv infusion of PGI 2 slightly increased oxygenation parameters. A significant increase in Pao 2/FiO 2 up to 32.4±3.1 kPa was observed during PGI 2 aerosol delivery (p< 0.01); iv PGI 2 decreased MAP from 11.5±0.39 kPa to 9.8±0.66 kPa (p< 0.05) and MPAP from 5.8±0.53 kPa to 4.5±0.66 kPa, respectively (p< 0.05). PGI 2 aerosol delivery significantly decreased the MPAP to 3.7±0.53 kPa (p< 0.05) without influencing the MAP. It was concluded that inhaled NO and inhaled PGI 2 act as selective pulmonary vasodilators in acute respiratory failure with pulmonary hypertension resulting in improved oxygenation mainly due to improved mismatch of pulmonary perfusion and ventilation. Intravenous PGI 2 improves oxygenation and pulmonary hemodynamics to a lesser extent than aerosolized PGI 2 and has the risk of systemic hypotension at a higher dose.