Introduction. The risk of developing transfusion-related complications, especially alloimmunization, is an ongoing concern for transfusion-dependent patients. It is important to determine the rate of alloimmunization and autoimmunization in Al-Ahsa Region, Saudi Arabia, where sickle cell disease (SCD) and thalassemia incidence rates are the highest in Saudi Arabia. Methods. A cross-sectional study was conducted to review the transfusion history of patients with SCD and thalassemia at the King Fahad Hospital (KFH) in Al-Ahsa, Saudi Arabia. 364 transfusion-dependent patients were included in this study. Results. Alloimmunization rates in patients with SCD and thalassemia were 16.7% and 11.97%, respectively, while autoimmunization rates in patients with SCD and thalassemia were 5.3% and 0.7%, respectively. The most frequent alloantibodies among the study participants were against Kell, Rh blood group systems. Conclusion. Blood transfusion-related alloimmunization and autoimmunization compromise the proper management of chronically transfused patients. Ideally, extended matched phenotyping should be implemented to prevent alloimmunization and reduce the risk of developing blood transfusion-related alloantibodies.