Abstract Rationale There are several approaches to select the optimal positive end-expiratory pressure (PEEP), resulting in different PEEP levels. The impact of different PEEP settings may extend beyond respiratory mechanics, affecting pulmonary hemodynamics. Objectives To compare PEEP levels obtained with three titration strategies—(i) highest respiratory system compliance (CRS), (ii) electrical impedance tomography (EIT) crossing point; (iii) positive end-expiratory transpulmonary pressure (PL)—in terms of regional respiratory mechanics and pulmonary hemodynamics. Methods Experimental studies in two porcine models of acute lung injury: (I) bilateral injury induced in both lungs, generating a highly recruitable model (n = 37); (II) asymmetrical injury, generating a poorly recruitable model (n = 13). In all experiments, a decremental PEEP titration was performed monitoring PL, EIT (collapse, overdistention, and regional ventilation), respiratory mechanics, and pulmonary and systemic hemodynamics. Measurements and main results PEEP titration methods resulted in different levels of median optimal PEEP in bilateral lung injury: 14(12–14) cmH2O for CRS, 11(10–12) cmH2O for EIT, and 8(8–10) cmH2O for PL, p < 0.001. Differences were less pronounced in asymmetrical lung injury. PEEP had a quadratic U-shape relationship with pulmonary artery pressure (R2 = 0.94, p < 0.001), right-ventricular systolic transmural pressure, and pulmonary vascular resistance. Minimum values of pulmonary vascular resistance were found around individualized PEEP, when ventilation distribution and pulmonary circulation were simultaneously optimized. Conclusions In porcine models of acute lung injury with variable lung recruitability, both low and high levels of PEEP can impair pulmonary hemodynamics. Optimized ventilation and hemodynamics can be obtained simultaneously at PEEP levels individualized based on respiratory mechanics, especially by EIT and esophageal pressure.