Previous studies demonstrated that high-frequency oscillatory ventilation using the open lung concept (OLC) resulted in superior gas exchange and a reduction in ventilator-induced lung injury (VILI). We hypothesized that these beneficial effects could also be achieved by applying the OLC during positive pressure ventilation. After repeated whole-lung-lavage, newborn piglets were assigned to either OLC positive pressure ventilation (PPV(OLC)), OLC high-frequency oscillatory ventilation (HFOV(OLC)), or conventional positive pressure ventilation (PPV(CON)) and ventilated for 5 h. In both OLC groups, collapsed alveoli were actively recruited and thereafter stabilized using the lowest possible airway pressures. In the PPV(CON) group, ventilator settings were adjusted to prevent critical hypoxia. Airway pressure, blood gas analysis, pressure-volume curve, and alveolar protein infiltration was recorded. A lung injury score was used for histologic comparison. Mean airway pressures were comparable in the three ventilation groups over time (1.2-1.5 kPa). Arterial oxygenation increased to mean values above 60 kPa in both OLC groups compared with 10 kPa in the PPV(CON) group (p < 0.001). Maximal lung compliance was superior in both OLC groups (PPV(OLC): 91 +/- 23; HFOV(OLC): 90 +/- 31 mL/kPa/kg, p < 0.01) compared with the PPV(CON) group (39 +/- 14 mL/kPa/kg). Alveolar protein infiltration was significantly reduced in the PPV(OLC) group (0.33 +/- 0.10 mg/mL, p < 0.01) and the HFOV(OLC) group (0.40 +/- 0.13 mg/mL, p < 0.01) compared with the PPV(CON) group (0.70 +/- 0.15 mg/mL). Lung injury scores were significantly higher in the PPV(CON) group (33.5 +/- 9.5, p < 0.01) compared with both OLC groups (PPV(OLC): 10.5 +/- 2.6; HFOV(OLC): 11 +/- 2.2). There were no differences between the two OLC groups. We conclude that, in surfactant-depleted newborn piglets, application of the OLC during PPV is feasible and results in superior gas exchange and a reduction in VILI compared with conventional PPV. These beneficial effects are comparable to HFOV.