Determining which patients with ARDS are most likely to benefit from lung recruitment maneuvers is challenging for physicians. The aim of this study was to assess whether the single-breath simplified decremental PEEP maneuver, which evaluates potential lung recruitment, may predict a subject's response to lung recruitment maneuvers, followed by PEEP titration. We conducted a pilot prospective single-center cohort study with a 3-step protocol that defined sequential measurements. First, potential lung recruitment was assessed by the single-breath maneuver in the volume controlled mode. Second, the lung recruitment maneuver was performed in the pressure controlled mode, with a fixed driving pressure of 15 cm H2O and a maximum PEEP of 30 cm H2O. Third, the lung recruitment maneuver was followed by decremental PEEP titration to determine the optimal PEEP, defined as the lowest driving pressure. Responders to the lung recruitment maneuver were defined by an improvement in PaO2 /FIO2 > 20% between the baseline state and the end of the PEEP titration phase. Forty-two subjects with moderate-to-severe ARDS were included. The mean ± SD lung recruitment was 149 ± 104 mL. A threshold lung recruitment of 195 mL (area under the receiver operator characteristic curve 0.62, 95% CI 0.43-0.80) predicted a positive response to the maximal lung recruitment maneuver. The lung recruitment maneuver, followed by PEEP titration, resulted in a modification of PEEP in 74% of the subjects. PEEP was increased in more than two thirds of the responders and decreased in almost half of the non-responders to the lung recruitment maneuver. In addition, a decrease in driving pressure and an increase in respiratory system compliance were reported in 62% and 67% of the subjects, respectively. The single-breath maneuver for evaluating lung recruitability predicted, with poor accuracy, the subjects who responded to the lung recruitment maneuver based on PaO2 /FIO2 improvement. Nevertheless, the lung recruitment maneuver, followed by PEEP titration, improved ventilator settings and respiratory mechanics in a majority of subjects.