Saline lung lavage yields a widely accepted animal model of respiratory insufficiency, suitable for evaluation of respiratory therapies. It is reported that PLV and HFOV improve oxygenation more and with less histologic lung injury than conventional gas ventilation (GV) in this model. This study compares the two techniques in ten anaesthetized and paralysed piglets (age 8-16 days, BW: 2.8-4.0 kg). Lung injury was induced by repeated saline lung lavage (PaO2<10 kPa for 15 minutes during GV 40× 26/6 cm H2O; I:E=1:1; FiO2=1.0). Five piglets were rescued with PLV: a perfluorocarbon FRC (FC-75 [3M-Company]) was instilled over 30 mins and maintained during GV (40× PIP/4 cm H2O; I:E=1:1; FiO2). PIP was manipulated to optimize PaO2 while maintaining normocapnia. Five piglets received HFOV (10 Hz; FiO2=1.0) using a high volume strategy. Mean airway pressure was increased as needed to achieve a PaO2 of ≥53 kPa. The amplitude of the piston-oscillator was altered in order to maintain normocapnia. Gas exchange was assessed at 10 and 30 mins, 1, 2, 3, and 4 hrs. Lung histology was performed after perfusion-fixation. Base line and post-injury blood gases were not different between the treatment groups. PaCO2 and pH were not different between PLV and HFOV group at any time. After initiation of therapy, both groups showed an increase in PaO2, which was significantly higher in the HFOV group after 30 mins, 1, 3, and 4 hours. Likewise, AaDO2 and A/a O2 ratio were lower at the same time points. Venous admixture (physiologic shunt) in the HFOV group was lower at 3 and 4 hours when compared to the PLV group (Mann-Whitney U test). Histomorphology revealed local desquamation of bronchiolar epithelium in both groups. Areas of inhomogeneous alveolar expansion were seen irrespective of the therapeutic strategy. Oxygenation seems superior during HFOV when compared to PLV. However, the gas exchange indices used reflect not only the gas exchange efficacy of the lung but also the diffusion conductance of the perfluorocarbon liquid. Without measuring diffusion capacity, the venous admixture and diffusion component cannot be distinguished. After 4 hours of both therapies, the histologic findings consistent with the primary insult are still present.