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Over the past decade, veno-arterial extracorporeal membrane oxygenation (VA-ECMO) has expanded rapidly as a salvage strategy to provide temporary circulatory and respiratory support allowing cardiac function recovery or bridging to additional therapeutic alternatives in patients with refractory cardiogenic shock. Peripheral access using the femoral vein and artery (FA) is the most widely used method for the initiation of VA-ECMO in adult patients.1 When venous blood is drained from the inferior caval vein (IVC), the patient is at risk of developing differential oxygenation meaning a low oxygenation of the upper part of the body, while the lower part has high oxygenation. Differential oxygenation might cause insufficient oxygen supply to the heart and brain and affect the prognosis of patients. Understanding mechanism and appropriate management of differential oxygenation are critical to favorable outcomes in patients undergoing peripheral VA-ECMO.