Background Hemolytic transfusion reactions due to red blood cell (RBC) alloantibodies are one of the leading causes of transfusion-associated death. RBC alloantibodies also cause significant morbidity in the form of delayed hemolytic transfusion reactions. Herein, we present the case of one allo-immunized patient with severe anemia, who had to wait 3 months to receive a blood transfusion due to the unavailability of compatible blood in the United States. Case Presentation A 59-year-old female with a history of chronic anemia requiring frequent transfusions, and end-stage kidney disease (ESRD) on hemodialysis (HD) presented to the hospital with complaints of fatigue and worsening anemia (hemoglobin Hb < 6mg/dl). She denied chest pain, shortness of breath, syncope, and active bleeding. She had consulted 3 different hospitals in New York requesting a blood transfusion, which hadn’t been done due to the unavailability of compatible blood. Laboratory results showed severe normocytic, normochromic anemia (Hb 5.0 g/dl) and a low reticulocyte count of 2.55%. Haptoglobin, lactate dehydrogenase, and bilirubin were within normal limits, ruling out hemolysis. Endoscopy and colonoscopy were negative for gastrointestinal bleeding. Iron, B12, and folate levels were found to be normal; all of which were suggestive of chronic disease anemia. The patient’s blood group was A, RhD negative. She was found to have antibodies against I, JKa, U, E, S and s antigens. The NY Blood Center was contacted, confirming the unavailability of RhD-negative, compatible packed red blood cell units (PRBC). The patient’s sister was tested and found to have compatible blood for donation. 1 PRBC was administered 2 weeks after hospital admission, after which the patient was stable to continue HD. Discussion The prevalence of alloimmunization in chronic transfusion patients is around 2- 8%. Alloimmunization risk is determined by the differences between donor and recipient RBC antigens, recipient genetic characteristics, and recipient inflammatory state at the time of initial antigen exposure. In our case, the patient had an increased risk for alloimmunization due to a history of multiple transfusions, female sex, and being RhD negative. Conclusion Alloimmunization can lead to significant morbidity in chronic transfusion patients due to a lack of compatible blood units. It is imperative to establish strategies to decrease primary RBC alloimmunization and mitigate the dangers of existing RBC alloantibodies in this population. Both antigen-matched transfusion and using leukocyte filters during transfusion might represent effective strategies to prevent alloimmunization due to white blood cells.