Management of pulmonary vascular resistance in neonates with congenital heart disease is important for stabilization before and after surgical interventions. Thus, we determined which combina tion of positive end-expiratory pressure ventilation and fraction of oxygen in the inspired air increases pulmonary vascular resistance without compromising delivery of oxygen to the tissue. Eight piglets were anesthetized, intubated and ventilated. Pulmonary flow and pulmonary arterial and left atrial pressures were monitored continuously. At all levels of inspired oxygen (1.00, 0.21 and 0.15), ventilation at a pressure of 15 cm of water increased pulmonary vascular resistance. At all levels of positive pressure ventilation, a fraction of 0.15 of inspired oxygen increased pulmonary vascular resistance. The combination of a ventilatory pressure of 15 cm of water and inspired oxygen of 1.00, or ventilatory pressure at 5 cm of water and oxygen delivery of 0.15, produced similar changes in pulmonary vascular resistance (19.1 ± 2.8 vs. 20.0 ± 3.8 mmHg/(L/min)) and cardiac output (0.78 ± 0.07 vs. 0.93 ± 0.10 L/min) but, the higher level of positive pressure plus 1.00 inspired oxygen gave a significantly higher arterial oxygen saturation (0.99 ± 0.03 vs. 0.72 ± 0.19%) and delivery of oxygen to the tissues (13.7 ± 2.9 vs. 7.4 ± 1.5 ml 02/min, p<0.05). Thus, both high positive pressure ventilation and hypoxia increase pulmonary vascular resistance. Only high pressure ventilation plus high concentrations of inspired oxygen, however, increased pulmonary vascular resistance without compromising delivery of oxygen, suggesting that this combination is a superior means of increasing pulmonary vascular resistance.