Background and Objectives The field of transfusion medicine started out with whole blood transfusion to treat severe anaemia and other deficiencies, and then transitioned to component therapy, largely leaving the practice, and experiences, of whole blood transfusions behind. Currently, the field is circling back and whole blood is gaining ground as an alternative to massive transfusion protocols. Materials and Methods Herein we describe a severely anaemic paroxysmal nocturnal haemoglobinuria (PNH) patient initially suspected of suffering from renal haemorrhage, receiving a standard low‐titre group O whole blood transfusion during pre‐hospital transportation. Results Following the transfusion, the patient suffered a clinically unmistakable haemolytic transfusion reaction requiring supportive treatment in the intensive care unit. Clinical observations are consistent with an acute haemolytic reaction. The haemolysis was likely due to minor incompatibility between the plasma from the transfused whole blood and the patient's PNH red cells. Recovery was uneventful. Conclusion This revealed an unappreciated contraindication to minor incompatible whole blood transfusion, and prompted a discussion on the distinction between whole blood and erythrocyte concentrates, the different indications for use and the importance of emphasizing these differences. It also calls attention to patient groups where minor incompatibility can be of major importance.