Background: Blood transfusions are a life-saving measure to replace blood lost through severe bleeding or as a life-saving treatment for various hematological conditions. Blood transfusions are high-risk procedures. One of these risks is alloimmunization. Alloimmunization is an immune response to foreign antigens after exposure to genetically different cells or tissues. Alloimmunization is a frequent undesirable outcome of a blood transfusion. In this study, we investigated the frequency of alloimmunization and the factors associated with the development of antibodies infrequently transfused patients. Materials and Methods: A descriptive cross-sectional study carried out in Khartoum, Sudan between November 2017 and March 2018. The study population included 97 multi-transfused patients (Solid tumors, 41; Sickle cell anemia, 31; Leukemia; 25), 52 males and 45 females whose ages ranged between 3-81 years and each subject received a minimum of 2 units of RBCs. The number of blood units transfused varied among patients from 2 to over 20 units depending on the underline disease treatment needs. Antibody screen was performed using four-cell commercially prepared Grifols reagent RBCs and gel impregnated with antihuman globulin. Results: The overall alloimmunization frequency was 22.7%. The alloimmunization frequency in Sickle cell anemia patients was 29.0%, solid tumors patients; 21.9%, and 16.0% in leukemic patients. Alloimmunization frequency was independent of the number of units transfused or gender (p value= 0.071, 0.942), respectively. Conclusion: Sudanese multi-transfused patients have higher rates of alloimmunization compared to other countries. It is our recommendation that pretransfusion protocols must include antibody screening. Timely antigen typing of donor's blood and to transfuse only antigen-negative blood.