We have previously demonstrated that rapid improvements in gas exchange and lung mechanics in various lung injury models may follow lung lavage with a synthetic surfactant which includes the KL4 peptide. This peptide has many of the physico-chemical properties of Surfactant Protein B. In this study we wished to determine if modest increases in PEEP would allow faster removal from the lungs of the instilled fluid load and reduce the physiologic instability seen during the lavage procedure. Methods: 8 newborn piglets were instrumented under fentanyl anesthesia with arterial and pulmonary artery catheters. Assisted ventilation with a neonatal ventilator was commenced and 3 mL/kg 30% human meconium was instilled followed after 20 minutes by a further 3 mL/kg. The animals were then monitored until PaO2 was less than 100 mmHg in an FiO2 of 1.0. They were then allocated to either a PEEP of 6 or 8 cmH2O for the remainder of the study. Lung lavage with a dilute preparation of KL4 (2.5 mg/mL) was performed with initial instillation of 8 mL/kg with the animal on one side followed by drainage of the surfactant and suctioning of the airway. This was followed by instillation of a second dose of 8mL/kg with the animal lying on its other side. A second identical lavage with the 2.5 mg/mL concentration was followed by a third with a more concentrated (10 mg/mL) solution. The animals were then monitored for 2 hours with no changes in ventilator settings. Results: The lowest oxygen saturation during the lavage itself was 62.6 (SD 11.4)% in the PEEP 6 group and 84.7 (SD 9.6)%, significantly improved p<0.0001, in the PEEP 8 group. At the end of the procedure the PaO2 was significantly improved in the PEEP 8 group 95 (SD 27) mmHg compared to the PEEP 6 group 69 (SD 17) mmHg. One hour later the PaO2 in the PEEP 8 animals was 247 (SD 155) mmHg and in the PEEP 6 group it was 121 (SD 95) mmHg, p<0.05. Pulmonary artery pressure increased slightly during the lavage procedure, and the increases were not different between groups. Conclusion. Lung lavage with KL4 surfactant produces a rapid improvement in gas exchange which is further augmented by a PEEP of 8 cmH2O in a newborn piglet meconium aspiration model.