To study the effect of different high-frequency oscillatory ventilation parameters on airway pressure, we measured oscillatory pressure amplitude ([Paw[) and mean airway pressure (Paw) at three sites in open-chested normal rabbits: proximal, trachea, and alveolus. Five animals were studied to test a new pleural capsule design, which was then used in two groups of animals to measure right upper (n = 4) or middle (n = 5) lobe alveolar pressures. Animals were randomly sequenced through combinations of frequency (10, 15, and 20 Hz) and fractional inspiratory time (Ti) (0.3 and 0.5) while normoxic and eucapnic. During capsule testing, we noted that alveolar pressures increased (p less than 0.05) with increasing capsule mass, suggesting that compressive forces from the capsule may alter the capsule measurement. We thus used a low-mass (430 mg) transducer system in the rabbit high-frequency oscillatory ventilation experiments. Using multifactorial analysis of variance, we found significant main effects of Ti on Paw, and of measurement site on both [Paw[ and Paw (all p less than 0.009). Frequency did not influence variations in either [Paw[ or Paw. For both Ti settings, alveolar upper lobe Paw was lower compared with that of the middle lobe (p less than 0.0005). Lengthening Ti (0.3 to 0.5) increased tracheal Paw in each capsule group (p less than 0.0005). At Ti = 0.5, tracheal Paw exceeded Paw measured proximally (p less than 0.05). Our data support in vivo alveolar Paw inhomogeneity and demonstrate significant changes in pressures within the lung related to Ti during high-frequency oscillatory ventilation.