We studied healthy and saline lavaged rabbits during high frequency oscillatory ventilation to determine what combination of frequency (f), tidal volume (Vt), and mean airway pressure (Paw) produced the lowest peak-to-peak alveolar pressure amplitude (Palv) and physiologic blood gas tensions. Sinusoidal volume changes were delivered through a tracheostomy by a piston pump driven by a linear motor. Tracheal pressure amplitude (Ptr) was measured through a tracheal catheter and alveolar pressure amplitude was measured in a capsule glued to the right lower lobe. Pao2, Paco2, Ptr, and Palvwere measured at the following settings: FiO2=0.5, frequency 2-28 Hz, V, 1-3 mL/kg (50 150% dead space) and Paw5-15 cm H2O. Many combinations of frequency and Vtresulted in the same Pao2 and Paco2. Paw had a large effect on Palvand minimal effect on blood gas tensions. In lavaged rabbits, the composite variable f X V,2 described the trends in Pa)v and blood gas tensions. As the product of fx Vt2 increased, Pao2initially increased and then decreased, whereas Paco2decreased and Palvincreased. No single combination of frequency, Vtand Paw simultaneously provided the lowest Palvand physiologic blood gas tensions. Adequate blood gas tensions and low Palvwere obtained at frequencies less than 12 Hz, a V, of 2 mL/kg and a Paw of 10 cm H2O. In healthy and lavaged rabbits Pao2increased and Paco2decreased as frequency increased at lower V1Pao2decreased as frequency increased at higher Vtin lavaged rabbits only. Palvtended to be greater in lavaged rabbits.