Background: Ventilation with low tidal volume (VT) is well recognized as a protective approach to patients with acute respiratory distress syndrome (ARDS), but the optimal level of positive end-expiratory pressure (PEEP) remains uncertain. This study aims to evaluate two protective ventilatory strategies sequentially applied in patients with early ARDS. Methods: In this prospective cohort study, fifteen patients were ventilated during 24h with positive end-expiratory pressure (PEEP) adjusted according to the ARDSnet low-PEEP table (ARDSnet-24h). During the next 24h, nine patients with PaO2/FIO2 ratio below 350 mmHg were ventilated with PEEP titrated according to the Open Lung Concept protocol (ARDSnet+OLC). In the other six patients, regardless of their PaO2/FIO2 ratio, the ARDSnet remained for a further 24 h (ARDSnet-48h). Ventilatory variables, arterial bloodgas and cytokine were obtained at baseline, 24 and 48h. Additionally, whole-lungcomputed tomography was acquired at 24 and 48h. Results: A sustained improvement in PaO2/FIO2 ratio (P=0.008) with a decrease in collapsed regions (P=0.008) was observed in the ARDSnet+OLC group compared with the ARDSnet-24h group. A reduction in IL-6 in plasma (P<0.02) was observed throughout the protocol in the ARDSnet+OLC group. Compared with the ARDSnet-48h group, the ARDSnet+OLC presented smaller amounts of collapsed areas (P=0.018) without significant differences in hyperinflated regions and in driving and plateau pressures. Conclusions: In this set of patients with early ARDS, mechanical ventilation with an individually tailored PEEP sustained improved pulmonary function with better aeration, without significant increase in hyperinflated areas”