With the general aim of obtaining clinically relevant information on the use of high-frequency oscillation (HFO), we examined the effects of altering oscillatory frequency (f), tidal volume (VT), and mean airway pressure (Paw) on gas exchange in rabbits, both before and after altering the animal's pulmonary mechanics by saline induced lung injury. Twenty-seven combinations of f (5, 8, 12 Hz), VT (0.5, 1, 2 mL/kg), and Paw (5, 10, 13 cm H2O) were used. Acute pulmonary injury was induced by instilling 10 mL/kg of warm saline into the lung. Gas exchange was assessed by steady-state levels of arterial oxygen tension (PaO2) and carbon dioxide tension (PaCO2). Arterial PaO2 was independent of f or VT before or after lung injury; it was independent of Paw before injury but highly dependent on Paw after lavage. The difference was presumably related to lung volume recruitment. Arterial PaCO2 was dependent on f and VT but independent of Paw at any time. The relationship was modeled by the equation PaCO2 alpha fa. VTb where the exponents a = -0.4 and b = -0.6. Our technique of a standardized saline instillation gave a reproducible and stable model of lung injury. In damaged rabbit lungs the principles of HFO appear to be similar to conventional mechanical ventilation; oxygenation depends on Paw and inspired oxygen concentration, while CO2 removal is determined by f and VT.