Background: Driving pressure (Delta Prs) across the respiratory system ă is suggested as the strongest predictor of hospital mortality in ă patients with acute respiratory distress syndrome (ARDS). We wonder ă whether this result is related to the range of tidal volume (VT). ă Therefore, we investigated.Prs in two trials in which strict ă lungprotective mechanical ventilation was applied in ARDS. Our working ă hypothesis was that.Prs is a risk factor for mortality just like ă compliance (Crs) or plateau pressure (Pplat, rs) of the respiratory ă system. ă Methods: We performed secondary analysis of data from 787 ARDS patients ă enrolled in two independent randomized controlled trials evaluating ă distinct adjunctive techniques while they were ventilated as in the low ă VT arm of the ARDSnet trial. For this study, we used VT, positive ă end-expiratory pressure (PEEP), Pplat, rs, Crs,Delta Prs, and ă respiratory rate recorded 24 hours after randomization, and compared ă them between survivors and nonsurvivors at day 90. Patients were ă followed for 90 days after inclusion. Cox proportional hazard modeling ă was used for mortality at day 90. If colinearity between.Delta Prs, Crs, ă and Pplat, rs was verified, specific Cox models were used for each of ă them. ă Results: Both trials enrolled 805 patients of whom 787 had day-1 data ă available, and 533 of these survived. In the univariate analysis,Delta ă Prs averaged 13.7 +/- 3.7 and 12.8 +/- 3.7 cmH2O (P = 0.002) in ă nonsurvivors and survivors, respectively. Colinearity between Delta Prs, ă Crs and Pplat, rs, which was expected as these variables are ă mathematically coupled, was statistically significant. Hazard ratios ă from the Cox models for day-90 mortality were 1.05 (1.02-1.08) (P = ă 0.005), 1.05 (1.01-1.08) (P = 0.008) and 0.985 (0.972-0.985) (P = 0.029) ă for.Prs, Pplat, rs and Crs, respectively. PEEP and VT were not ă associated with death in any model. ă Conclusions: When ventilating patients with low VT,.Prs is a risk factor ă for death in ARDS patients, as is Pplat, rs or Crs. As our data ă originated from trials from which most ARDS patients were excluded due ă to strict inclusion and exclusion criteria, these findings must be ă validated in independent observational studies in patients ventilated ă with a lung protective strategy.