Purpose: Percutaneous cannulation is increasingly used for veno-arterial extracorporeal membrane oxygenation (VA-ECMO). However, there is limited evidence about the benefit of this approach compared with conventional surgical cannulation. By using a large international database, this study was designed to compare in-hospital outcomes in cardiac shock patients who received femoro-femoral VA-ECMO with percutaneous versus surgical cannulation. Methods: Adults with refractory cardiogenic shock treated with percutaneous (percutaneous group) or surgical (surgical group) femoro-femoral VA-ECMO between January 2008 and December 2019 were extracted from the international Extracorporeal Life Support Organization registry. The primary outcome was in-hospital mortality. Multivariable logistic regression analyses were performed to assess the association between percutaneous cannulation and in-hospital outcomes. Results: Among 12,592 patients meeting study inclusion, 9,249 (73%) underwent percutaneous cannulation. The proportion of patients undergoing percutaneous cannulation increased from 32% to 84% over the study period (p < 0.01 for trend). In-hospital mortality (53% vs 58%; p < 0.01), cannulation site bleeding (19% vs 22%; p < 0.01), and systemic infection (8% vs 15%; p < 0.01) occurred less frequently in the percutaneous group compared to the surgical group. In adjusted analyses, percutaneous cannulation was independently associated with lower rates of in-hospital mortality (odds ratio [OR] 0.76; 95% CI 0.70-0.84; p < 0.01), cannulation site bleeding (OR 0.70; 95% CI 0.60-0.80; p < 0.01) and systemic infection (OR, 0.63; 95% CI 0.54-0.74; p < 0.01). Severe limb ischemia was more frequently observed in the percutaneous group (5% vs 3%; p < 0.01). However, this association was not significant in adjusted analysis (OR 1.28; 95% CI 0.93-1.62; p = 0.15). Conclusions: Compared with surgical cannulation, percutaneous cannulation was independently associated with lower in-hospital mortality and fewer complications.