Acute lung injury caused by tidal volume ventilation in the premature lamb with respiratory distress syndrome (RDS) is characterized by progessive deterioration in gas exchange and lung inflammation. Inhaled nitric oxide (iNO) improves gas exchange and decreases lung neutrophil accumulation in premature lambs with RDS. Mechanical lung recruitment techniques such as high-frequency oscillatory ventilation (HFOV) and partial liquid ventilation (PLV) also decrease lung injury and improve gas exchange in experimental models of neonatal respiratory failure. We hypothesized that two lung recruitment strategies (HFOV and PLV) would have similar effects on gas exchange and lung inflammation, and would augment the response to iNO. We studied the individual and combined effects of iNO, HFOV, and PLV (perflubron) in 31 extremely premature lambs (115 d, 0.78 term) using seven mechanical ventilation protocols. Four groups were treated with conventional ventilation (control CV, CV + iNO, CV + PLV, and CV + PLV + iNO). Three groups were treated with HFOV (control HFOV, HFOV + iNO, HFOV + PLV). Control CV animals had progressive deterioration in gas exchange over the 4-h study period (a/AO2 at 4 h = 0.06 +/- 0.01). In contrast, both HFOV and CV + PLV caused sustained improvements in oxygenation at 4 h (HFOV a/AO2 = 0. 27 +/- 0.06, CV + PLV a/AO2 = 0.25 +/- 0.04; p < 0.01 versus CV). Both lung recruitment strategies improved oxygenation when combined with iNO (5 ppm). Lung neutrophil accumulation was reduced by HFOV, PLV, and iNO compared to CV. We conclude that HFOV and PLV with perflubron cause similar improvements in gas exchange and lung inflammation in the premature lamb with severe RDS, and both strategies augment the oxygenation response to iNO.