Traditional lung management during extracorporeal membrane oxygenation (ECMO) calls for low inspiratory and expiratory pressures with low ventilator rate to achieve lung rest. However, rapid weaning of pressures to severely injured lungs commonly leads to marked increase in pulmonary opacification as seen on chest x-ray and loss of volume. We postulated that a sufficiently high level of PEEP could prevent this deterioration. Forty-six newborns, who required ECMO therapy for refractory respiratory failure, were maintained on 8 to 14 cm H2O PEEP. The peak pressure was 20 to 24 cm H2O, rate 10 to 15 breath/min, and FIO2 0.21. Forty-one (89%) of 46 patients survived to discharge. The duration of ECMO was significantly decreased compared to the national average (82.4 +/- 43 vs. 117.5 +/- 59 h). The lungs of most patients remained adequately expanded and free of severe pulmonary opacification. Eleven of 40 patients did show significant worsening of chest x-ray compared to baseline, but only one of 18 who were on PEEP of greater than or equal to 12 cm H2O showed such deterioration. No unexpected complications were encountered. These data suggest that the use of high PEEP during ECMO safely prevents deterioration of lung function and promotes more rapid lung recovery. PEEP levels of 12 to 14 cm H2O appear to be most effective.