Infants with congenital diaphragmatic hernia (CDH) die, because their lungs are hypoplastic and their pulmonary vascular resistance remains elevated after birth. In human newborns, it is difficult to appreciate the benefit of new therapeutic approaches, because the pathological findings are not uniform, the disease is rare and the clinical criteria for poor prognosis with conventional therapy are uncertain. To study the benefit of high-frequency ventilation (HFV) the use of Tolazoline in CDH, we created a diaphragmatic defect in sheep fetuses at 0.6 gestation and studied full-term newborns after a caesarian section. A sternotomy was performed to place catheters and flow probes on the aorta and pulmonary artery and to clamp the ductus arteriosus and the left pulmonary artery. Twins were used as control, and the CDH lambs were either ventilated with conventional ventilation (CV) or HFV. 23 ewes were operated upon with a 22% abortion rate and 31 newborn lambs (10 controls and 21 CDH) were studied. A complete gasometric and hemodynamic study was performed in 23 lambs (7 controls, 8 CDH with CV and 8 CDH with HFV). Clinical and pathological findings of the lambs with CDH were very similar to severe CDH in humans with bilateral lung hypoplasia, severe respiratory distress, high pulmonary vascular resistance and severe hypoxemia. HFV dramatically improved CO2 elimination, allowed less aggressive ventilation, and was associated with higher flows and lower systemic and pulmonary vascular resistance. However, HFV did not improve oxygenation leaving the newborn with severe hypoxemia associated with massive intrapulmonary foramen ovale shunting from right to left.