In 12 patients undergoing extracorporeal membrane oxygenation for treatment of severe acute respiratory distress syndrome (ARDS), we examined the effects of independent variations in mixed venous oxygen tension (PvO2) and inspired oxygen fraction (FIO2) on the distribution of ventilation and perfusion as assessed by the multiple inert gas elimination technique. Reducing the oxygen concentration of the constant gas stream through the membrane lungs allowed us to decrease the PvO2 by approximately 20 Torr independently of variations in cardiac output and FIO2 as well as to augment FIO2 without influencing PvO2. The interventions did not induce any change in heart rate or systemic or pulmonary hemodynamics. In general, neither during mechanical ventilation at FIO2 of 0.6 nor during mechanical ventilation at FIO2 of 1.0 did the reduced PvO2 cause variations in the distribution of pulmonary blood flow in our patients with severe ARDS. Nevertheless, in individual patients, decreasing PvO2 or ventilation at FIO2 of 1.0 was associated with changes in intrapulmonary shunt. Therefore, we conclude that it is not possible to predict the influence of such interventions in pulmonary gas exchange in the individual patient suffering from ARDS. Differences in the regulation of the local distribution of blood flow caused by the disease itself might explain this phenomenon.