Uncontrolled systemic-to-pulmonary shunt results in decreased systemic flow during extracorporeal life support (ECLS). Ligation of systemic-to-pulmonary shunts during ECLS is associated with poor outcome and is not always readily achieved. In ex vivo preparations, alveolar hypoxia results in pulmonary vasoconstriction despite normoxic pulmonary perfusate. We hypothesized that anoxic ventilation would result in reduced pulmonary shunting and increased systemic flow during ECLS in piglets with systemic-to-pulmonary shunt. Four piglets were placed on ECLS with right and left atrial drainage. A shunt was created between the bicarotid trunk and pulmonary artery, using 5-mm ePTFE tubing. Inspired oxygen was reduced to <1% for 10 minutes, then returned to room air; pH, hematocrit, temperature, ventilatory pressures, and total pump flow were maintained constant. Systemic arterial pressure and right atrial return volume and hemoglobin saturation were measured: All decreased significantly upon shunt unclamping. Anoxic ventilation caused increased systemic pressure (34 vs. 28 mm Hg, p < 0.05), flow (335 vs. 278 mL/min, p < 0.05), and systemic venous saturation (53% vs. 48%, p = 0.13) compared with room air ventilation. In conclusion, anoxic ventilation during normoxic ECLS in subjects with systemic-to-pulmonary shunts results in a significant and potentially clinically useful reduction in pulmonary shunting.