Partial liquid ventilation (PLV) improves oxygenation in various animal models of respiratory insufficiency. The aim of this study was to compare the effects of conventional ventilation (CV), high frequency oscillatory ventilation (HFOV), and PLV combined with CV or HFOV on gas exchange and histopathology. Thirty anaesthetised newborn piglets (mean weight 1.94 kg, age 1-3 days) were randomized in five groups of six animals: CV, CV + surfactant (S), HFOV+S, PLV/CV, and PLV/HFOV. Thirty min after lung injury had been induced with repeated saline lavage, specific ventilatory treatment was initiated. Three animals of the CV group died within the 24 h study period, whereas none died in any of the other groups. The oxygenation index (OI) and the PaO2/FIO2 ratio improved significantly within 30 min in all groups, but not in the CV group. After 24 h all oxygenation parameters were better in the PLV groups than in CV or CV+S (P < 0.05). No differences in gas exchange were noted between HFOV+S and PLV/CV. The combination of PLV with HFOV led to an increased PaO2/FIO2 ratio when compared with PLV/CV and with HFOV+S (P < 0.05). All PLV treated animals had significantly less lung injury in the upper and lower lobes compared with gas-ventilated animals by histologic semi-quantitative lung injury score (P < 0.01) and in the lower lobes by morphometry (P < 0.001). In conclusion, HFOV+S and PLV either with CV or HFOV are effective techniques to provide adequate gas exchange in S-deficient lungs compared with CV with and without S. However, lung injury was significantly improved in both PLV treated groups compared with HFOV+S and the CV groups.