Background: The Wra blood group antigen is a low-frequency antigen. Antibody screening sets used in pretransfusion laboratory investigations usually do not contain a Wr(a+) cell. If subsequent cross-matching is performed without indirect antiglobulin test (IAT), Wra antibodies reacting with donor red blood cells (RBCs) will be missed. For reasonable economic and time-saving arguments the risk of missing the detection of a potential clinically relevant antibody is worldwide accepted. Case Report: A 66-year-old women with a negative antibody screen rapidly deteriorated after she received two units of RBCs for symptomatic anemia after hip surgery. Diagnosis of a transfusion reaction was obscured by pre-existing and nonspecific symptoms. Laboratory investigation indicated acute hemolysis. Cross-matching in IAT was positive for the first unit, and an extended antibody identification panel showed reactivity with Wr(a+) cells. The patient did not respond to supportive therapy and died within 48 h after the start of transfusion. Conclusion: This dramatic case provides further evidence on the clinical relevance of Wra blood group antibodies. In addition, it underlines the clinical importance of risk awareness in the blood transfusion chain and the possible complexity in relation to patient monitoring in daily transfusion practice.