Extracorporeal membrane oxygenation is essential for the treatment of refractory cardiopulmonary failure. Its use may be complicated by worse haemorrhagic complications exacerbated by extracorporeal membrane oxygenation–related therapeutic anticoagulation. Progressive technological advancements have made extracorporeal membrane oxygenation components less thrombogenic, potentially allowing its application with temporary avoidance of systemic anticoagulants. A systematic review of all the available experiences, reporting the use of extracorporeal membrane oxygenation without systemic anticoagulation in the published literature was performed. Only patient series were included, irrespective of the clinical indication. The survival, extracorporeal membrane oxygenation system–related dysfunction and complications rates, as well as in-hospital outcome, were analysed. Six studies were selected for the analysis. Veno-arterial extracorporeal membrane oxygenation was used in 84% of patients, while veno-venous extracorporeal membrane oxygenation was applied in the remaining cases. Anticoagulation was avoided because of the high risk of bleeding after cardiac surgery (64%), active major bleeding (23%) or presence of severe traumatic injury (9%). Duration of support ranged from 0.3 to 1128 h. Heparin was antagonized by protamine in all the post-cardiotomy cases. Successfully extracorporeal membrane oxygenation weaning was achieved in 74% of the treated cases, with a hospital discharge of 58% of patients. Rates of extracorporeal membrane oxygenation malfunctioning due to clot formation and blood transfusion requirement varied remarkably in the published series. Extracorporeal membrane oxygenation without systemic anticoagulation appears feasible in selected circumstances. Further investigations are warranted to elucidate actual aspects regarding extracorporeal membrane oxygenation system performance, related adverse events and benefits associated with this management.