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Abstract Background Although lung protection with low tidal volume and limited plateau pressure (P plat) improves survival in acute respiratory distress syndrome patients (ARDS), the best way to set positive end-expiratory pressure (PEEP) is still debated. Methods This study aimed to compare two strategies using individual PEEP based on a maximum P plat (28–30 cmH2O, the Express group) or on keeping end-expiratory transpulmonary pressure positive (0–5 cmH2O, P Lexpi group). We estimated alveolar recruitment (Vrec), end-expiratory lung volume and alveolar distension based on elastance-related end-inspiratory transpulmonary pressure (P L,EL). Results Nineteen patients with moderate to severe ARDS (PaO2/FiO2 < 150 mmHg) were included with a baseline PEEP of 7.0 ± 1.8 cmH2O and a PaO2/FiO2 of 91.2 ± 31.2 mmHg. PEEP and oxygenation increased significantly from baseline with both protocols; PEEP Express group was 14.2 ± 3.6 cmH2O versus 16.7 ± 5.9 cmH2O in P Lexpi group. No patient had the same PEEP with the two protocols. Vrec was higher with the latter protocol (299 [0 to 875] vs. 222 [47 to 483] ml, p = 0.049) and correlated with improved oxygenation (R 2 = 0.45, p = 0.002). Two and seven patients in the Express and P L,expi groups, respectively, had P L,EL > 25 cmH2O. Conclusions There is a great heterogeneity of P Lexpi when P plat is used to titrate PEEP but with limited risk of over-distension. A PEEP titration for a moderate positive level of P Lexpi might slightly improve alveolar recruitment and oxygenation but increases the risk of over-distension in one-third of patients.