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Background: Positive end-expiratory pressure (PEEP) can potentially modulate inspiratory effort (ΔPes), which is the major determinant of self-inflicted lung injury., Research Question: Does high PEEP reduce ΔPes in patients with moderate-to-severe ARDS on assisted ventilation?, Study Design and Methods: Sixteen patients with Pao 2 /Fio 2  ≤ 200 mm Hg and ΔPes ≥ 10 cm H 2 O underwent a randomized sequence of four ventilator settings: PEEP = 5 cm H 2 O or PEEP = 15 cm H 2 O + synchronous (pressure support ventilation [PSV]) or asynchronous (pressure-controlled intermittent mandatory ventilation [PC-IMV]) inspiratory assistance. ΔPes and respiratory system, lung, and chest wall mechanics were assessed with esophageal manometry and occlusions. PEEP-induced alveolar recruitment and overinflation, lung dynamic strain, and tidal volume distribution were assessed with electrical impedance tomography., Results: ΔPes was not systematically different at high vs low PEEP (pressure support ventilation: median, 20 cm H 2 O; interquartile range (IQR), 15-24 cm H 2 O vs median, 15 cm H 2 O; IQR, 13-23 cm H 2 O; P = .24; pressure-controlled intermittent mandatory ventilation: median, 20; IQR, 18-23 vs median, 19; IQR, 17-25; P = .67, respectively). Similarly, respiratory system and transpulmonary driving pressures, tidal volume, lung/chest wall mechanics, and pendelluft extent were not different between study phases. High PEEP resulted in lower or higher ΔPes, respiratory system driving pressure, and transpulmonary driving pressure according to whether this increased or decreased respiratory system compliance (r = -0.85, P < .001; r = -0.75, P < .001; r = -0.80, P < .001, respectively). PEEP-induced changes in respiratory system compliance were driven by its lung component and were dependent on the extent of PEEP-induced alveolar overinflation (r = -0.66, P = .006). High PEEP caused variable recruitment and systematic redistribution of tidal volume toward dorsal lung regions, thereby reducing dynamic strain in ventral areas (pressure support ventilation: median, 0.49; IQR, 0.37-0.83 vs median, 0.96; IQR, 0.62-1.56; P = .003; pressure-controlled intermittent mandatory ventilation: median, 0.65; IQR, 0.42-1.31 vs median, 1.14; IQR, 0.79-1.52; P = .002). All results were consistent during synchronous and asynchronous inspiratory assistance., Interpretation: The impact of high PEEP on ΔPes and lung stress is interindividually variable according to different effects on the respiratory system and lung compliance resulting from alveolar overinflation. High PEEP may help mitigate the risk of self-inflicted lung injury solely if it increases lung/respiratory system compliance., Trial Registration: ClinicalTrials.gov; No.: NCT04241874; URL: www., Clinicaltrials: gov., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: D. L. G. has received speaking fees from Gilead, Intersurgical, MSD, and GE; and reports having received travel accommodation by Fisher and Paykel, outside the submitted work. M. A. has received personal fees by Maquet and a research grant by Toray, outside the submitted work. D. L. G. and M. A. disclose a research grant by GE, outside the submitted work. None declared (G. B., V. G., A. B., L. D. C., T. R., L. S. M., L. M., T. M., G. S., G. D. P., M. A. P., R. R. D. S. S., L. B.)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)