Background: Changing trunk inclination affects lung function in patients with ARDS. However, its impacts on PEEP titration remain unknown. The primary aim of this study was to assess, in mechanically ventilated patients with COVID-19 ARDS, the effects of trunk inclination on PEEP titration. The secondary aim was to compare respiratory mechanics and gas exchange in the semi-recumbent (40° head-of-the-bed) and supine-flat (0°) positions following PEEP titration. Methods: Twelve patients were positioned both at 40° and 0° trunk inclination (randomized order). The PEEP associated with the best compromise between overdistension and collapse guided by Electrical Impedance Tomography (PEEPEIT) was set. After 30 min of controlled mechanical ventilation, data regarding respiratory mechanics, gas exchange, and EIT parameters were collected. The same procedure was repeated for the other trunk inclination. Results: PEEPEITwas lower in the semi-recumbent than in the supine-flat position (8 ± 2 vs. 13 ± 2 cmH2O,p< 0.001). A semi-recumbent position with optimized PEEP resulted in higher PaO2:FiO2(141 ± 46 vs. 196 ± 99,p= 0.02) and a lower global inhomogeneity index (46 ± 10 vs. 53 ± 11,p= 0.008). After 30 min of observation, a loss of aeration (measured by EIT) was observed only in the supine-flat position (−153 ± 162 vs. 27 ± 203 mL,p= 0.007). Conclusions: A semi-recumbent position is associated with lower PEEPEITand results in better oxygenation, less derecruitment, and more homogenous ventilation compared to the supine-flat position.