Recruitment maneuvers are used in patients with ARDS to enhance oxygenation and lung mechanics. Heterogeneous lung and chest-wall mechanics lead to unpredictable transpulmonary pressures and could impact recruitment maneuver success. Tailoring care based on individualized transpulmonary pressure might optimize recruitment, preventing overdistention. This study aimed to identify the optimal transpulmonary pressure for effective recruitment and to explore its association with baseline characteristics. We performed post hoc analysis on the Esophageal Pressure Guided Ventilation (EpVent2) trial. We estimated the dose-response relationship between end-recruitment end-inspiratory transpulmonary pressure and the change in lung elastance after a recruitment maneuver by using logistic regression weighted by a generalized propensity score. A positive change in lung elastance was indicative of overdistention. We examined how patient characteristics, disease severity markers, and respiratory parameters predict transpulmonary pressure by using multivariate linear regression models and dominance analyses. Of 121 subjects, 43.8% had a positive change in lung elastance. Subjects with a positive change in lung elastance had a mean ± SD transpulmonary pressure of 15.1 ± 4.9 cm H2O, compared with 13.9 ± 3.9 cm H2O in those with a negative change in lung elastance. Higher transpulmonary pressure was associated with increased probability of a positive change in lung elastance (adjusted odds ratio 1.35 per 1 cm H2O of transpulmonary pressure, 95% CI 1.13-1.61; P = .001), which indicated an S-shaped dose-response curve, with overdistention probability > 50% at transpulmonary pressure values > 18.3 cm H2O. The volume of recruitment was transpulmonary pressure-dependent (P < .001; R2 = 0.49) and inversely related to a change in lung elastance after adjusting for baseline lung elastance (P < .001; R2= 0.43). Negative correlations were observed between transpulmonary pressure and body mass index, PEEP, Sequential Organ Failure Assessment score, and PaO2 /FIO2 , whereas baseline lung elastance showed a positive correlation. The body mass index emerged as the dominant negative predictor of transpulmonary pressure (ranking 1; contribution to R2 = 0.08), whereas pre-recruitment elastance was the sole positive predictor (contribution to R2 = 0.06). Higher end-recruitment transpulmonary pressure increases the volume of recruitment but raises the risk of overdistention, providing the rationale for transpulmonary pressure to be used as a clinical target. Predictors, for example, body mass index, could guide recruitment maneuver individualization to balance adequate volume gain with overdistention.