Acute lung injury caused by conventional mechanical ventilation in the premature lamb with hyaline membrane disease (HMD) is characterized by progessive deterioration in gas exchange and marked lung neutrophil influx. Past studies have demonstrated that both high frequency oscillatory ventilation (HFOV) when employed using a “high volume strategy” and partial liquid ventilation (PLV) decrease lung injury and improve gas exchange in experimental models of neonatal respiratory failure. However, the relative effectiveness of these two therapies in minimizing lung injury and improving gas exchange in severe HMD is unknown. We hypothesized that these two different lung recruitment strategies would have similar effects on gas exchange and reduction in lung inflammation. We studied the effects of HFOV and PLV in 15 extremely premature lambs (115 days, 0.78 term; 147 days = term) using 3 mechanical ventilation protocols. Premature animals were treated with exogenous surfactant (Infasurf) before beginning conventional ventilation (CV, N=5), HFOV (N=5), or PLV(perflubron) with conventional ventilation (N=5) for 4 hours with FiO2=1.00. Ventilator settings were adjusted to optimize oxygenation and ventilation over the 4 hour study period. Arterial blood gases were recorded hourly. Lung neutrophil accumulation was measured using a myeloperoxidase assay (MPO). CV animals had progressive deterioration in gas exchange over the 4 hour study period (a/AO2 at 4 hours=0.065±0.014). In contrast, both HFOV(using a high volume strategy) and PLV caused sustained improvements in oxygenation at 4 hours (HFOV a/AO2 = 0.272±0.057, PLV a/AO2 = 0.250±0.039; P<.01 vs. CV). Lung neutrophil accumulation(MPO, units/gram lung tissue) was markedly reduced by both HFOV(0.06±0.06) and PLV (0.16±0.08) compared to CV(0.53±0.20, P<.05 vs. HFOV and PLV). Histologic examination showed more homogenous inflation with both HFOV and PLV compared to controls. We conclude that HFOVand PLV cause: 1) similar improvements in gas exchange, and 2) equivalent attenuation of lung inflammation in the premature lamb with severe HMD. We speculate that these lung recruitment strategies could favorably modulate the inflammatory component of lung injuy in clinical HMD.