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Aims: This study aimed to investigate incidence and predictors of weaning failure and in-hospital death after successful weaning from veno-arterial extracorporeal membrane oxygenation (VA-ECMO) in patients with cardiogenic shock (CS)., Methods and Results: Overall, 685 patients with CS treated with VA-ECMO from 23 tertiary care centres in 7 countries were analysed (median age 57 [interquartile range 49-66] years, 542 [79.1%] male, median lactate 7.6 [interquartile range 4.1-12.7] mmol/L). The cause of CS was acute myocardial infarction in 438 (63.9%) patients, and 431 (62.9%) patients presented with cardiac arrest. A total of 410 patients (59.9%) were successfully weaned from VA-ECMO, whereas in 275 patients (40.1%) weaning failed (i.e. patients died on or within 48 h after VA-ECMO support). Of the successfully weaned patients, 150 (36.6%) died before hospital discharge. On multivariable logistic regression, predictors for both patient groups varied: age (per 10 years, odds ratio [OR] 1.49, 95% confidence interval [CI] 1.25-1.76; p < 0.001) and cardiac arrest before VA-ECMO implantation (OR 1.64, 95% CI 1.01-2.64; p = 0.04) were associated with weaning failure, whereas lactate clearance within 24 h after VA-ECMO initiation was associated with successful weaning (OR 0.21, 95% CI 0.1-0.44; p < 0.001). In-hospital death after successful weaning was more likely with higher age (per 10 years, OR 1.56, 95% CI 1.24-1.97; p < 0.001), renal replacement therapy (OR 2.56, 95% CI 1.4-4.68; p = 0.002) and bleeding events (OR 2.93, 95% CI 1.4-6.14; p = 0.004)., Conclusion: Weaning from VA-ECMO fails in 40% of patients treated with VA-ECMO for CS. When successful, survival after VA-ECMO weaning mostly depends on age and the incidence of device- and shock-related complications., (© 2025 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)