Objective: To compare the changes in respiratory mechanics within the breathing cycle in healthy lungs between gas ventilation and partial liquid ventilation using a special forced-oscillation technique. Design: Prospective animal trial. Settings: Animal laboratory in a university setting. Subjects: A total of 12 newborn piglets (age, <12 hrs; mean weight, 725 g) Interventions: After intubation and instrumentation, lung mechanics of the anesthetized piglets were measured by forced-oscillation technique at the end of inspiration and the end of expiration. The measurements were performed during gas ventilation and 80 mins after instillation of 30 mL/kg perfluorocarbon PF 5080. Measurements and Main Results: Brief flow pulses (width, 10 msec; peak flow, 16 L/min) were generated by a jet generator to measure the end-inspiratory and the end-expiratory respiratory input impedance in the frequency range of 4-32 Hz. The mechanical variables resistance, inertance, and compliance were determined by model fitting, using the method of least squares. At least in the lower frequency range, respiratory mechanics could be described adequately by an RIC single-compartment model in all piglets. During gas ventilation, the respiratory variables resistance and inertance did not differ significantly between end-inspiratory and end-expiratory measurements (mean [SD]: 4.2 [0.7] VS. 4.1 [0.6] kPa·L^-1·sec, 30.0 [3.2] vs. 30.7 [3.1] Pa·L^-1·sec², respectively), whereas compliance decreased during inspiration from 14.8 (2.0) to 10.2 (2.4) mL·kPa^-1·kg^-1 due to a slight lung overdistension. During partial liquid ventilation, the end-inspiratory respiratory mechanics was not different from the end-inspiratory respiratory mechanics measured during gas ventilation. However, in contrast to gas ventilation during partial liquid ventilation, compliance rose from 8.2 (1.0) to 13.0 (3.0) mL·kPa^-1·kg^-1 during inspiration. During expiration, when perfluorocarbon came into the upper airways, both resistance and inertance increased considerably (mean with 95% confidence interval) by 34.3% (23.1%-45.8%) and 104.1% (96.0%-112.1%), respectively. Conclusions: The changes in the respiratory mechanics within the breathing cycle are considerably higher during partial liquid ventilation compared with gas ventilation. This dependence of lung mechanics from the pulmonary gas volume hampers the comparability of dynamic measurements during partial liquid ventilation, and the magnitude of these changes cannot be detected by conventional respiratory-mechanical analysis using time-averaged variables.