Different arterial cannulation strategies are feasible for veno-arterial extracorporeal membrane oxygenation (VA-ECMO) in postcardiotomy shock. We aimed to analyze potential benefits and safety of different arterial cannulation strategies. We identified 158 patients with postcardiotomy cardiogenic shock requiring VA-ECMO between 01/10 and 01/19. Eighty-eight patients were cannulated via axillary or femoral artery (group P), and 70 centrally via the ascending aorta directly or through an 8 mm vascular graft anastomosed to the ascending aorta (group C). Demographics and operative parameters were similar. Change of cannulation site for Harlequin's syndrome or hyperperfusion of an extremity occurred in 13 patients in group P but never in group C (p = 0.001). Surgical revision of cannulation site was also encountered more often in group P than C. The need for left ventricular (LV) unloading was similar between groups, whereas surgical venting was more often implemented in group C (11.4% vs. 2.3, p = 0.023). Stroke rates, renal failure, and peripheral ischemia were similar. Weaning rate from ECMO (52.9% vs. 52.3%, p = NS) was similar. The 30 day mortality was higher in group P (60% vs. 76.1%, p = 0.029). Central cannulation for VA-ECMO provides antegrade flow without Harlequin's syndrome, changes of arterial cannula site, and better 30 day survival. Complication rates regarding need for reexploration and transfusion requirements were similar.