High-frequency oscillatory ventilation (HFOV) causes less severe lung injury than conventional mechanical ventilation (CMV) but the optimal frequency for HFOV has not been determined. We hypothesized that 15 Hz HFOV would be more protective than 5 Hz HFOV in a rabbit model of acute lung injury. Surfactant-depleted rabbits were ventilated at 15 Hz or 5 Hz HFOV for 4 h, or not ventilated, to characterize the extent of lung injury before HFOV. PaO(2) and PaCO(2) were measured throughout the experiment, and lung myeloperoxidase (MPO) activity, neutrophil infiltration, and histopathological changes were determined. There were no statistically significant differences in PaO(2) and PaCO(2) between groups (p > 0.05). Neutrophil counts (p = 0.013), airway injury scores (p = 0.007), airspace injury scores (p = 0.029), and total lung injury scores (p = 0.014) differed between non-HFO-ventilated and HFOV animals. Comparing the 2 HFOV regimens, 15 Hz ventilation yielded a lower tissue neutrophil score (p = 0.005). MPO activity, neutrophil count, airway injury score, airspace injury score, and total lung injury score parameters did not differ significantly between the HFOV groups (p > 0.150). We concluded that both frequencies of HFOV efficiently restored O(2) and CO(2) exchange in a rabbit model of severe lung injury, and that 5 Hz HFOV increased neutrophil infiltration relative to 15 Hz HFOV.