OBJECTIVES: Transfusion-related ABO incompatibility reactions may result in significant morbidity and mortality. Hospitalized elderly and immunocompromised (IC) patients may be at an increased risk due to high blood utilization. The study objectives were to assess ABO incompatibility transfusion reactions and potential risk factors among hospitalized U.S. elderly during 2007-2018. METHODS: Our retrospective claims-based study utilized large Medicare databases. Blood transfusions were identified by procedure and revenue center codes, and ABO incompatibility reactions via diagnosis codes. Study evaluated reaction rates (per 100,000 inpatient transfusion stays) among Medicare beneficiaries ages 65 and older, overall and by calendar year, demographics, IC status, blood components and units transfused. Fisher’s exact tests were performed to compare rates, and Cochran-Armitage tests assessed trends over time, by age and transfusion volume. RESULTS: Of 17,771,193 inpatient transfusion stays, 233 had ABO incompatibility transfusion reaction(s), a rate of 1.3 per 100,000 stays, with annual rates ranging from 1.2 in 2007 to 2.0 in 2018 (p=0.821). Reaction rates by number of units transfused (1, 2-4, 5-9, >9) were: 0.6, 1.0, 2.1, and 3.8 (p<0.001). The highest reaction rates by blood component groups were: RBCs and platelets (7.5); RBCs, plasma, and platelets (2.1); RBCs and plasma (1.4); and RBCs only (1.3). For ages 65-69, 70-74, 75-79, 80-84, and ≥85, rates were 2.0, 1.3, 1.3, 1.2, and 0.9, respectively (p<0.001). Whites and non-whites had rates: 1.4 and 1.0 (p=0.09). Among IC, reaction rate was 3.2 vs. 0.9 for non-IC beneficiaries, [rate ratio 3.4 (95%CI 2.6-4.5)]. CONCLUSIONS: Our 12-year population-based study on transfusion-related ABO incompatibility reactions shows an increasing risk with greater number of units transfused and a declining risk with advancing age. The study identified significantly higher reaction risk in IC beneficiaries and suggests substantially increased risk among recipients of RBCs and platelets, as well as possible effects of demographic characteristics, which need further investigations.