Acute respiratory distress syndrome (ARDS) increases mortality in patients with multiorgan dysfunction syndrome (MODS). This study evaluates the feasibility of intrapleural steroid instillation (IPSI) in patients with ARDS and MODS unresponsive to conventional extracorporeal membrane oxygenation (ECMO). Ninety-two of 467 patients who underwent ECMO between 2005 and 2009 had ARDS, and 30 consecutive adult patients of these 92 patients with severe ARDS and MODS were retrospectively analyzed in this study. Nine of these 30 patients, who did not respond to therapy and whose condition deteriorated, were managed with IPSI. All patients met the inclusion criteria of hemodynamic instability with high catecholamine infusion requirement and 100% oxygen demand in ventilation and ECMO flow. On initial diagnosis of ARDS, no differences in prognostic scorings were observed in patients who underwent conventional treatment (n = 21) and those who underwent IPSI (n = 9). Blood oxygenation, tidal volume, changing in chest radiographic findings, and survival rates were analyzed. The primary outcome was survival until discharge from the hospital. Pulmonary radiographic appearance improved after 3 days of IPSI treatment (P = 0.008); the ratio of arterial partial pressure of oxygen to fraction of inspired oxygen also increased significantly after 5 days of IPSI treatment (P = 0.028). Moreover, the 28-day mortality rate (P = 0.017), 60-day mortality rate (P = 0.003), and survival rate (78% vs. 19%; P = 0.003) significantly improved in patients undergoing IPSI, which therefore appears to be an easily implemented and highly effective treatment for patients with severe ARDS in combination with MODS, particularly in patients who fail to respond to conventional treatment.