Anti-E alloantibody has been one of the most frequently detected clinically significant alloantibodies in previous studies. Red blood cell (RBC) transfusion is unique in its common intravenous introduction of foreign E antigen and provides a valuable opportunity to study the human immunologic response to intravenous foreign E antigen. Patients exposed to foreign E antigen while receiving RBC transfusions are at risk of forming anti-E alloantibody. Valid estimates of anti-E alloimmunization risk are clinically important, but the forming mechanism of anti-E alloimmunization remains unclear. Here, we screened 516 inpatients at risk of exposure to foreign E antigen while receiving RBC transfusions and monitored the development of anti-E alloantibody for up to two years after left hospital. However, only 2 cases of anti-E alloimmunization were identified in this study. Patients who received RBC transfusion had a very high risk of exposure to foreign E antigen, but the anti-E alloantibody production incidence was very low and few anti-E alloantibodies were produced within 3 to 6 months after RBC transfusion in this study. Further research would contribute to our knowledge of the anti-E alloimmunization mechanism and prevent anti-E development, which would be significantly useful in clinical for transfusions, obstetric management, and the evaluation and management of transfusion reactions in laboratory and institutional resources and cost reduction in healthcare system.