Veno-venous ECMO (VV-ECMO) requires extracorporeal blood drainage, oxygenation, and return. Cannulation of the vena cava or right atrium is necessary. We investigated the optimal cannulation sites for gas exchange in VV-ECMO and found that draining from the inferior vena cava and returning to the superior vena cava achieved the best oxygenation and carbon dioxide removal.