Abstract Background Recently published randomized controlled trials and an individual patient data meta-analysis showed that the routine use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) did not reduce mortality compared to medical therapy alone in patients with acute myocardial infarction complicated by cardiogenic shock (AMI-CS). Purpose The aim of this study was to investigate as to whether possible VA-ECMO-related medical complications might be associated with an increased mortality risk, which might explain the observed equipoise among mortality outcomes between VA-ECMO and usual care in patients with AMI-CS. Methods Using data from the randomized ECLS-SHOCK trial (Extracorporeal Life Support in Infarct-Related Cardiogenic Shock), which compared routine VA-ECMO use versus medical therapy alone. Causal mediation analyses (primary analysis; VA-ECMO-related complications used as a mediator), logistic regression and causes of death analyses (secondary analyses) were utilised to test potential effects of possible VA-ECMO-related complications on 30-day mortality. Analyses were adjusted for risk factors of bleeding and vascular complications. Results In total, 417 patients were included in this analysis. Moderate and severe bleeding as well as peripheral vascular complications requiring intervention were identified as possible VA-ECMO-related complications. A total of 88 patients (21.1%) developed possible VA-ECMO-related complications, which mostly occurred within five days after randomisation and more frequently in the VA-ECMO group than in the control group: 49 (23.4%) vs. 20 (9.6%) patients, p<0.001 for bleeding and 23 (11.0%) vs. 8 (3.8%) patients, p=0.01 for peripheral vascular complications, respectively. Causal mediation analyses revealed no significant mediation effect of possible VA-ECMO-related complications on 30-day mortality (p=n.s.; Figure). Logistic regression and causes of death analyses of possible VA-ECMO-related complications confirmed no significant associations between the incidence of VA-ECMO-related complications and mortality (p=n.s.). Conclusion VA-ECMO use in patients with AMI-CS was associated with increased incidences of moderate to severe bleeding as well as vascular complications warranting intervention. In this causal mediation analysis, VA-ECMO-related complications do not appear to mediate an increased mortality risk.