Perfluorochemical liquid (PFC) liquids or aerosols are used for assisted ventilation, drug delivery, lung cancer hyperthermia and pulmonary imaging. The aim of this study was to investigate the effect of PFC liquid on the inertance (I) of the respiratory system in newborn piglets using partial liquid ventilation (PLV) with different volumes of liquid. End-inspiratory (I _in) and end-expiratory (I_ex) inertance were measured in 15 ventilated newborn piglets (age < 12 h, mean weight 724 ± 93 g) by brief flow pulses before and 80 min after PLV using a PFC volume (PF5080, 3 M) of 10 ml kg^-1 (N = 5) or 30 ml kg^-1 (N= 10). I was calculated from the imaginary part of the measured respiratory input impedance by regression analysis. Straight tubes with 2-4 mm inner diameter were used to validate the equipment in vitro by comparison with the analytically calculated values. In vitro measurements showed that the measuring error of I was <5% and that the reproducibility was better than 1.5%. The correlation coefficient of the regression model to determine I was >0.988 in all piglets. During gas ventilation, I_in and I_ex (mean ± SD) were 31.7 ± 0.8 Pa l^-1 s² and 33.3 ± 2.1 Pa l ^-1 s² in the 10 ml group and 32.4 ± 0.8 Pa l ^-1 s² and 34.0 ± 2.5 Pa l^-1 s ² in the 30 ml group. However, I of the 3 mm endotracheal tube (ETT) used was already 26.4 Pa l^-1 s² (about 80% of measured I). During PLV, there was a minimal increase of I_in to 33.1 ± 2.5 Pa l^-1 s² in the 10 ml group and to 34.5 ± 2.7 Pa l^-1 s² in the 30 ml group. In contrast, the increase of I_ex was dramatically larger (p < 0.001) to 67.7 ± 13.3 Pa l^-1 s² and to 74.8 ± 9.3 Pa l^-1 s ² in the 10 ml and 30 ml groups, respectively. Measurements of I by jet pulses in intubated small animals are reproducible. PFC increases the respiratory inertance, but the magnitude depends considerably on its spatial distribution which changes during the breathing cycle. Large differences between I_in and I_ex are an indicator for liquid in airways or the ETT.