ARDS places a significant burden on the health-care system, with an estimated prevalence of 7% of ICU admissions and an unacceptable hospital mortality rate of 50%.1Pulmonary and systemic inflammation are the pathophysiologic hallmarks of this syndrome,2and activation of the glucocorticoid receptor in pulmonary and circulating cells is an essential step in restoring homeostasis.3While changing the ventilator settings to low tidal volume reduces systemic inflammation with a favorable impact on survival,4a concomitant antiinflammatory pharmacologic intervention should lead to a more rapid resolution of ARDS and earlier extubation. Among the antiinflammatory drugs, glucocorticoids have been the most investigated treatment in ARDS. Early trials5–8 demonstrated that, when administered at high dose (eg, 30 mg/kg of body weight [2,100 mg for a patient weighing 70 kg] of methylprednisolone [or equivalent] per day for approximately 24 h) to cure or to prevent ARDS, glucocorticoids provided no survival benefit and even may have favored life-threatening superinfections. In the last 20 years, significant advances have been made in understanding the complex molecular mechanisms of action of glucocorticoids, while accumulated clinical data on low-dose, prolonged glucocorticoid treatment (methylprednisolone, 1 mg/kg/d [70 mg for a patient weighing 70 kg], or equivalent) in ARDS has shown significant improvement in inflammation and lung physiology with a favorable benefit/risk profile.16 Glucocorticoids modulate almost all steps of the inflammatory process through genomic and nongenomic actions. In patients with ARDS, moderate doses of glucocorticoids were associated with a progressive increase in glucocorticoid receptor-mediated activities leading to significant reductions in nuclear factor-κB DNA binding and transcription of tumor necrosis factor and interleukin-1β.10 Thereby, prolonged glucocorticoid treatment decreased both lung and circulating levels of various proinflammatory mediators at both early and late phases of the disease.10–16 In animal models of acute lung injury, early administration of glucocorticoids showed protective effects on lung parenchyma with maintenance of tissue impedance and extracellular matrix.15 In five randomized trials11–14,16 of patients with acute lung injury or ARDS, prolonged treatment with glucocorticoids in moderate doses consistently improved gas exchange, lung injury score, and dramatically shortened duration of mechanical ventilation. Glucocorticoid treatment prevented the dissemination of inflammation to extrapulmonary organs and decreased the prevalence of cardiovascular dysfunction.6–10,12 Needless to say, that for many physicians, a treatment that reduces pulmonary and systemic inflammation, improves lung mechanics and gas exchange, and prevents progression of multiple organ failure should become a standard of care for ARDS patients. The effect of prolonged glucocorticoid treatment on survival in ARDS remains controversial. In patients treated for persistent ARDS, ie, glucocorticoids were initiated after day 7 from the disease onset, one single-center randomized trial,11 showed dramatic increase in survival rate, whereas a recent multicenter trial13 did not show any evidence for a survival benefit, and even suggested that when glucocorticoids are administered very late after 2 weeks of progression of the disease, they may cause harm. There are significant differences in between-studies design that may account for this discrepancy in results on survival. Among them, too short of a period allowed to wean glucocorticoids in the ARDSnet trial,13and concomitant use of a neuromuscular blocking agent were the most important. The current study by Meduri et al14 in this issue of CHEST (see page 954) is the first multicenter randomized, placebo-controlled trial focusing on early and prolonged (2 weeks at full dose then tapered off > 2 weeks) treatment with low- dose glucocorticoids (1 mg/kg per day [70 mg/d for a patient weighing 70 kg] of methylprednisolone). This study confirms the benefit from glucocorticoids on physiologic parameters and on ARDS complications, and suggested that this treatment improved short-term and long-term survival. The potential survival benefit was in keeping with a recently published post hoc analysis,12 of a randomized trial of low-dose glucocorticoids for septic shock that included patients with ARDS and showed significant improvement in hospital and 1-year survival. Then, when data from these four randomized placebo-controlled trials on moderate dose of glucocorticoids for ARDS are pooled, accounting for 472 patients, the relative risk of short-term mortality was 0.81 (95% confidence interval, 0.66 to 0.99) in favor of treatment with glucocorticoids.11–19 Glucocorticoids may induce serious adverse events; among them, GI bleeding, superinfection, blunted febrile response, hyperglycemia, and muscle weakness deserve specific attention to be prevented. These drug-related adverse events should not discourage physicians from treating ARDS patients with glucocorticoids, similar to our approach with prolonged methylprednisone treatment in patients admitted to the ICU with acute exacerbation of asthma or COPD.