Objectives: To determine the efficacy of perfluorocarbon-associated gas exchange and the effects of inhaled nitric oxide during perfluorocarbon-associated gas exchange in the congenital diaphragmatic hernia lamb model. Design: Prospective, nonrandomized, controlled, nonhuman trial. Setting: Animal research facility. Subjects: Fetal lambs of 16 time-dated pregnant ewes, at 80 days gestation (term 140 to 145 days). Measurements and Main Results: The congenital diaphragmatic hernia lamb model was created in 16 animals. Twelve animals survived to be studied, All animals were mechanically ventilated for 4 hrs with a time-cycled, pressure-limited ventilator. Perfluorocarbon-associated gas exchange was started after 15 mins of ventilation (n = 6), Blood gases were analyzed at 30 mins and then hourly. The perfluorocarbon-associated gas exchange animals had dynamic compliance and tidal volumes measured, After 1 hr, inhaled nitric oxide (80 parts per million) was delivered to the perfluorocarbon-associated gas exchange animals for 10 mins. All blood gas parameters, including pH (6.72 +/- 0.06 vs, 7.14 +/- 0.07), Pco(2) (186 +/- 12 vs, 70.5 +/- 16.7 torr [24.8 +/- 1.6 vs, 9.5 +/- 2.1 kPa]), and Po-2 (48 +/- 17 vs. 156 +/- 48 torr [6.4 +/- 2.3 vs. 20.8 +/- 6.4 kPa]) were significantly improved in the perfluorocarbon-associated gas exchange-treated group at 4 hrs (p < .005), Dynamic compliance (0.13 +/- 0.02 vs, 0.32 +/- 0.06 mL/cm H2O/kg) and tidal volume (3.5 +/- 0.35 vs, 7.22 +/- 0.61 mL/kg) were also significantly (p < .001) increased in the perfluorocarbon-associated gas exchange group, In the perfluorocarbon-associated gas exchange animals, nitric oxide caused a significant (p < .05) increase in oxygenation and a reduction in pulmonary hypertension. This effect was reversed by stopping the inhaled nitric oxide. Conclusions: Perfluorocarbon-associated gas exchange significantly improved gas exchange, dynamic compliance, and tidal volumes, Furthermore, inhaled nitric oxide can be effectively delivered during perfluorocarbon-associated gas exchange to reduce pulmonary hypertension and enhance oxygenation.