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OBJECTIVES: Upper gastrointestinal bleeding (UGIB) is a common complication in adults treated with veno-arterial extracorporeal membrane oxygenation (VA-ECMO) for refractory cardiogenic shock or cardiac arrest. We aimed to determine risk factors, prevalence and outcomes associated with VA-ECMO-associated UGIB in adult patients. METHODS: We conducted a retrospective cohort study (2014–2022) on consecutive VA-ECMO patients in the medical and infectious disease intensive care unit of Bichat-Claude Bernard University Hospital, Paris, France. UGIB was defined as (i) an overt bleeding (haematemesis, melena, haematochezia) or (ii) acute anaemia associated with a lesion diagnosed on upper gastrointestinal endoscopy. VA-ECMO-associated UGIB was defined as an UGIB occurring during VA-ECMO, or up to 10 days after decannulation in patients weaned off extracorporeal membrane oxygenation (ECMO). Cause-specific models were used to identify factors associated with UGIB and death, respectively. RESULTS: Among the 455 patients included, 48 (10%) were diagnosed with UGIB after a median of 12 [7; 23] days following ECMO cannulation. Mortality occurred in 36 (75%) patients with UGIB and 243 (60%) patients without. UGIB patients had longer intensive care unit stays (32 [19; 60] vs 18 [7; 37] days; P < 0.01), longer ECMO (14 [9; 18] vs 7 [4; 11] days; P < 0.01) and mechanical ventilation durations (21 [16; 36] vs 10 [5; 20] days; P < 0.01), as compared to non-UGIB patients. Ninety upper gastrointestinal endoscopies were performed, and the most frequent lesions detected were gastro-duodenal ulcers (n = 23, 26%), leading to 11/90 therapeutic procedures. By multivariable analysis, a history of peptic ulcer [cause-specific hazard ratio (CSHR) 2.93, 95% confidence interval (CI) [1.01; 8.51]], a dual antiplatelet therapy (CSHR 2.0, 95% CI [1.07; 3.72]) and extracorporeal cardiopulmonary resuscitation (CSHR 2.78, 95% CI [1.42; 5.45]) were independently associated with an increased risk of UGIB. CONCLUSIONS: In adult patients under VA-ECMO, a history of gastric ulcer, dual antiplatelet therapy and extracorporeal cardiopulmonary resuscitation were independently associated with an increased risk of UGIB. This study highlights the potential role of acute ischaemia–reperfusion injury in the pathophysiology of VA-ECMO-associated UGIB. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is an emergency technique used in adult patients to treat refractory cardiogenic shock or refractory cardiac arrest [1]. [ABSTRACT FROM AUTHOR]