Previous studies exploring the utility of liquid breathing using perfluorocarbon have reported proximal airway pressures (Paw) as high as 70 Torr during inspiration, generating concern about the safety of this form of mechanical ventilation. Effects on the pulmonary capillary bed are, however, more likely related to alveolar pressure (PA) than to Paw, and data on PA during liquid breathing are limited. In this study in infant lambs, we reconstructed the pressure waveforms of PA during liquid breathing by using an occlusion technique and compared these with Paw waveforms. Peak PA (18.6 ± 10.4 Torr) was significantly less than peak Paw (31.5 ± 10.5 Torr, P < 0.001), indicating a large resistive pressure drop (14.4 ± 4.5 Torr) across the bronchial tree. Mean PA (mPA) was very similar to mean Paw (mPaw) [bias = -2.0 Torr, standard error of the average difference = 0.27 Torr, predictive value of mPaw for MPA (r2) = 0.978], suggesting that mPaw, which is easily measured, may be used to estimate mPA during perfluorocarbon liquid breathing. These data show that alveoli do not experience the same large swings in pressure as the proximal airway does during liquid breathing and that simple measurements of mPaw can be used to approximate mPA during liquid breathing.