Experimental and clinical evidence has demonstrated a strong association between dysregulated systemic inflammation and progression of acute respiratory distress syndrome (ARDS). In ARDS, glucocorticoid receptor-mediated downregulation of inflammation is essential to restore homeostasis and decrease morbidity and mortality. We review the findings of eight controlled studies (n = 569) evaluating treatment initiated before day 14 of ARDS. These trials consistently reported that treatment-induced reduction in systemic inflammation was associated with a significant improvement in ratio of partial arterial oxygen tension to fraction of inspired oxygen, and reductions in multiple organ dysfunction score, duration of mechanical ventilation and intensive care unit length of stay. Treatment was also associated with a marked reduction in the risk of death (relative risk: 0.68; 95% CI: 0.56-0.81; p < 0.001) and a sizable increase in mechanical ventilation-free days (weighted mean difference: 6.58 days; 95% CI: 2.93-10.23; p < 0.001); and intensive care unit-free days (weighted mean difference: 7.02 days; 95% CI: 3.20-10.85; p < 0.001). We recommend that prolonged methylprednisolone treatment, at an initial dose of 1 mg/kg/day in early ARDS and 2 mg/kg/day in unresolving ARDS, be delivered as an infusion to avoid glycemic variability, and that infection surveillance be strictly implemented to identify infections in the absence of fever.