The present authors hypothesised that in severe acute respiratory distress syndrome (ARDS), pronation may reduce ventilator-induced overall stress (i.e. transpulmonary pressure (PL)) and strain of lung parenchyma (i.e. tidal volume (VT)/end-expiratory lung volume (EELV) ratio), which constitute major ventilator-induced lung injury determinants. The authors sought to determine whether potential pronation benefits are maintained in post-prone semirecumbent (SRPP) posture under pressure-volume curve-dependent optimisation of positive end-expiratory pressure (PEEP). A total of 10 anesthetised/paralysed, mechanically ventilated (VT=9.0+/-0.9 mL(.)kg(-1) predicted body weight; flow=0.91 +/- 0.04 L(.)s(-1); PEEP=9.4 +/- 1.3 cmH(2)O) patients with early/severe ARDS were studied in pre-prone semirecumbent (SRBAS), prone, and SRPP positions. Partitioned respiratory mechanics were determined during iso-flow (0.91 L(.)s(-1)) experiments (VT varied within 0.2-1.0 L), along with haemodynamics, gas exchange, and EELV. Compared with SRBAS, pronation/SRPP resulted in reduced peak/plateau PL at VTS greater than or equal to 0.6 L; static lung elastance and additional lung resistance decreased and chest wall elastance (in prone position) increased; EELV increased (23-33%); VT/EELV decreased (27-33%); arterial oxygen tension/inspiratory oxygen fraction and arterial carbon dioxide tension improved (21-43/1014%, respectively), and shunt fraction/physiological dead space decreased (21-50/20-47%, respectively). In early/severe acute respiratory distress syndrome, pronation under positive end-expiratory pressure optimisation may reduce ventilator-induced lung injury risk. Pronation benefits may be maintained in post-prone semirecumbent position.