Because alveolar fluid clearance (AFC) is impaired in most patients with acute respiratory distress syndrome (ARDS) and is associated with higher mortality, we hypothesized that baseline plasma soluble receptor for advanced glycation end-products (sRAGE), a marker of lung epithelial injury and of impaired AFC, would predict mortality, independently of two key mediators of ventilator-induced lung injury such as driving pressure and tidal volume. We conducted a meta-analysis of individual data from 746 patients enrolled in eight prospective randomized and observational studies, and found that higher baseline plasma sRAGE was associated with higher 90-day mortality in patients with ARDS, independently of driving pressure and tidal volume, thus reinforcing the likely contribution of alveolar epithelial injury as an important prognostic factor in ARDS.