Abstract Background / Introduction The optimal vascular access site for percutaneous coronary interventions (PCI) in patients with acute myocardial infarction (AMI) complicated by cardiogenic shock (CS) remains uncertain. While observational data favor trans-radial access (TRA) due to lower complication rates and mortality, trans-femoral (TFA) PCI offers advantages such as shorter access and procedure times, along with quicker escalation to mechanical circulatory support (MCS). Purpose In this study, we aimed to investigate factors associated with a transfemoral approach and compare mortality rates between TRA and TFA in AMI-CS patients undergoing PCI. Methods Data from a nationwide registry of AMI-CS patients undergoing PCI (2017-2021) were analyzed. We compared patient demographics, procedural details, and outcomes between TRA and TFA groups. Logistic regression identified access site factors and radial-to-femoral cross-over predictors. Propensity score matched (PSM) analysis examined the impact of access site on mortality. Results Of 1562 patients, 45% underwent TRA PCI, with an increasing trend over time. TFA patients were more often female, had a history of coronary artery bypass grafting (CABG), lower blood pressure, higher resuscitation and intubation rates, and elevated lactate levels. After PSM, 30-day mortality was lower in TRA (33% vs. 46%, p <0.001). Predictors for cross-over included left coronary artery interventions, multivessel PCI, and MCS initiation. Conclusion Significant differences exist between TRA and TFA PCI in AMI-CS. TFA was more common in patients with worse hemodynamics and was associated with higher 30-day mortality compared to TRA. TRA should be the default access, given its feasibility and favorable outcomes in many patients.Baseline characteristicsPredictors for femoral access