A massive transfusion protocol can substantially improve survival of life‐threatening bleeding. This requires multidisciplinary cooperation, and a well‐organized transfusion service striving to integrate an effective antibody diagnosis and the supply of antigen‐negative red cell into the management of bleeding emergencies. Necessary prerequisites are an automated donor phenotype programme, an inventory strategy and a proactive patient assessment strategy. The donor screening secures a daily inventory to cover the most commonly needed antigen‐negative red cells. Moreover, a supply of frozen red cells with rare phenotypes, and an inter‐blood‐establishment cooperation may secure that rare blood can be provided. A proactive patient assessment should include screening of patients at risk of forming alloantibodies, identification of antibodies, and a transfusion strategy. Prior to surgery, the risk of bleeding and transfusion should be assessed. If antigen‐negative blood is limited or unavailable, relevant patient blood management measures should be undertaken. In the unexpected major bleeding, the massive transfusion protocol is activated, and transfusion of unmatched O blood may be necessitated. The clinical doctor is informed about incompatible transfusions and the patient is monitored to evaluate the consequences. Most often, haemolysis is mild, and may be alleviated by symptomatic treatment, or with immune‐suppressants. In the rare case of severe haemolysis, exchange transfusion of compatible blood may be performed. To provide a high level of care to bleeding patients with red cell antibodies, it is mandatory for the blood establishment to systematically organize donor screening, patient assessment, inventory and staff, and to communicate effectively with the clinically responsible doctors.