Venovenous extracorporeal gas exchange is increasingly used in awake, spontaneously breathing patients as a bridge to lung transplantation. Limited data are available on a similar use of extracorporeal gas exchange in patients with acute respiratory distress syndrome. The aim of this study was to investigate the use of extracorporeal gas exchange in awake, spontaneously breathing sheep with healthy lungs and with acute respiratory distress syndrome and describe the interactions between the native lung (healthy and diseased) and the artificial lung (extracorporeal gas exchange) in this setting. Laboratory investigation. Animal ICU of a governmental laboratory. Eleven awake, spontaneously breathing sheep on extracorporeal gas exchange. Sheep were studied before (healthy lungs) and after the induction of acute respiratory distress syndrome via IV injection of oleic acid. Six gas flow settings (1-10 L/min), resulting in different amounts of extracorporeal CO2 removal (20-100% of total CO2 production), were tested in each animal before and after the injury. Respiratory variables and gas exchange were measured for every gas flow setting. Both healthy and injured sheep reduced minute ventilation according to the amount of extracorporeal CO2 removal, up to complete apnea. However, compared with healthy sheep, sheep with acute respiratory distress syndrome presented significantly increased esophageal pressure variations (25 ± 9 vs 6 ± 3 cm H2O; p < 0.001), which could be reduced only with very high amounts of CO2 removal (> 80% of total CO2 production). Spontaneous ventilation of both healthy sheep and sheep with acute respiratory distress syndrome can be controlled via extracorporeal gas exchange. If this holds true in humans, extracorporeal gas exchange could be used in awake, spontaneously breathing patients with acute respiratory distress syndrome to support gas exchange. A deeper understanding of the pathophysiology of spontaneous breathing during acute respiratory distress syndrome is however warranted in order to be able to propose extracorporeal gas exchange as a safe and valuable alternative to mechanical ventilation for the treatment of patients with acute respiratory distress syndrome.