Background <p>Several approaches for setting PEEP in patients with (COVID-19-related) ARDS have been proposed. It is unclear whether a best approach exist, and how the recommended PEEP and resulting transpulmonary pressure, overdistension and collapse relate.</p> Objectives <p>To compare approaches based on electrical impedance tomography (EIT) (including targeting the crossing point of overdistension/collapse curves, EIT_CP) with targeting positive end-expiratory transpulmonary pressure (P_L,EE) and targeting highest respiratory system compliance (C_RS).</p> Methods <p>Post-hoc analysis of 29 patients with COVID-19-related ARDS from cohorts of two Dutch hospitals. Patients underwent a decremental PEEP trial, while EIT data and esophageal pressure data were recorded. We compared the recommended PEEP, as well as resulting P_L,EE and amounts of overdistension and collapse at the suggested PEEP.</p> Results <p>Targeting EIT_CP resulted in higher recommended PEEP (14 [12–16] cmH₂O) compared to a positive P_L,EE (12 [8–14] cmH₂O), while highest C_RS resulted in intermediate PEEP levels. Individually, the difference between the highest and lowest recommended PEEP level were 6 [4–8] cmH₂O. P_L,EE at the recommended PEEP was generally higher when targeting EIT_CP compared to and positive P_L,EE (1.4 [0.6–2.1] cmH₂O). The amount of collapse was lowest with EIT_CP (3.0 [2.0–4.0]%) and highest when targeting P_L,EE (5.4 [2.0–12.0]%). No significant differences in the amount of overdistension were found. Targeting positive P_L,EE resulted in 51% patients with high (&gt; 10%) values for either overdistension or collapse, more than any other method.</p> Conclusions <p>Targeting EIT_CP results in slightly higher recommended PEEP and P_L,EE levels compared to positive P_L,EE, leading to less collapse, but not more overdistension. EIT-based methods protect better against high values of either overdistension or collapse.</p>