To test the hypothesis that increased positive end-expiratory pressure (PEEP) could prevent deterioration of pulmonary function and lead to more rapid recovery of lung function, we randomly assigned 74 patients undergoing extracorporeal membrane oxygenation (ECMO) at four centers to receive either high (12 to 14 cm H2O) or low (3 to 5 cm H2O) PEEP. The two groups were similar in terms of weight, gestational age, diagnosis, and pre-ECMO course. All other aspects of care were identical. Dynamic lung compliance was measured at baseline and every 12 hours. Radiographs of the chest were obtained daily. Survival rates were similar in the two groups: 36 of 40 for low PEEP and 34 of 34 for high PEEP. The duration of ECMO therapy was 97.4 +/- 36.3 hours in the high-PEEP group and 131.8 +/- 54.5 hours in the low-PEEP group (p less than 0.01). Dynamic lung compliance throughout the first 72 hours of ECMO was significantly higher in patients receiving high PEEP. Radiographic appearance of the lungs correlated well with lung compliance: patients receiving high PEEP had significant deterioration of the radiographic score less frequently than those receiving low PEEP. High PEEP also was associated with significantly fewer complications. We conclude that PEEP of 12 to 14 cm H2O safely prevents deterioration of pulmonary function during ECMO and results in more rapid lung recovery than traditional lung management with low PEEP.