While plateau airway pressure alone is an unreliable estimate of lung overdistension inspiratory transpulmonary pressure (PL) is an important parameter to reflect it in patients with ARDS and there is no concensus about which computation method should be used to calculate it. Recent studies suggest that different formulas may lead to different tidal volume and PEEP settings. The aim of this study is to compare 3 different inspiratory PL measurement method; direct measurement (PL
D
), elastance derived (PL
E
) and release derived (PL
R
) methods in patients with multiple mechanical abnormalities. 34 patients were included in this prospective observational study. Measurements were obtained during volume controlled mechanical ventilation in sedated and paralyzed patients. During the study day airway and eosephageal pressures, flow, tidal volume were measured and elastance, inspiratory PL
E
, PL
D
and PL
R
were calculated. Mean age of the patients was 67 ± 15 years and APACHE II score was 27 ± 7. Most frequent diagnosis of the patients were pneumonia (71%), COPD exacerbation(56%), pleural effusion (55%) and heart failure(50%). Mean plateau pressure of the patients was 22 ± 5 cmH
2
O and mean respiratory system elastance was 36.7 ± 13 cmH
2
O/L. E
L
/E
RS
% was 0.75 ± 0.35%. Mean expiratory transpulmonary pressure was 0.54 ± 7.7 cmH
2
O (min: − 21, max: 12). Mean PL
E
(18 ± 9 H
2
O) was significantly higher than PL
D
(13 ± 9 cmH
2
O) and PL
R
methods (11 ± 9 cmH
2
O). There was a good aggreement and there was no bias between the measurements in Bland–Altman analysis. The estimated bias was similar between the PL
D
and PL
E
(− 3.12 ± 11 cmH
2
O) and PL
E
and PL
R
(3.9 ± 10.9 cmH
2
O) measurements. Our results suggest that standardization of calculation method of inspiratory PL is necessary before using it routinely to estimate alveolar overdistension.