Sickle cell disease (SCD) is a general term describing a group of inherited haemoglobin disorders which have in common the presence of HbS in the blood. Clinical manifestations of sickle cell disease are usually systemic with acute and chronic effects involving virtually every organ in the body. The clinical course is characterized by episodes of acute exacerbation of disease signs and symptoms (crisis) interspaced with periods of relative good health (steady state). Management of sickle cell disease requires a holistic approach involving various professionals. Blood transfusion is central in the prevention and treatment of complications of sickle cell disease. Sickle cell disease may be managed with simple (top-up) transfusion, exchange blood transfusion, or a chronic transfusion regime. However Blood transfusion may lead to development of an allo-antibody against the recipient’s red cells (alloimmunisation). The frequency of alloimmunisation has been extensively studied in different parts of the world, and indeed a few studies had been done in some parts of Nigeria. This study which is the first in Enugu, in the Eastern part of Nigeria attempted to find out how common alloimunisation is among patients with sickle cell disease who attend the University of Nigeria Teaching Hospital, the socio-demographic factors involved, the types of alloantibodies developed, and their clinical relevance. One hundred and twenty (120) patients with sickle cell disease were enrolled in the study: 80 patients who had previously been transfused and fulfilled the inclusion criteria were in the study group, and 40 patients who were never transfused formed the control group. Following informed consent, blood samples were obtained from the patients. The serum and cells were separated and stored appropriately. Antibody screening was done on the sera of all the patients, using commercially available Kitts (Dia-Screen gel cards) which contain Coombs reagent, enzymes and auto control, the ID-Diacells I, II and III (commercially prepared human cells) from Dia-Med co-operation. All the sera that gave positive reactions with antibody screening were subjected to antibody Identification using liss/Coombs gel cards and ID-Dia panel of cells 1-11 (commercially prepared human cells from the Dia-Med co-operation). Alloantibodies to erythrocytes were detected in 18.75% (15/80) of patients in study group (transfused patients) and 0% (0/40) of control group (untransfused patients). The relative risk was indefinitely large, and attributable risk (AR) was 18.75%. Three (3) autoantibodies were also found, two in the control 1 group and one in transfused group. Of the 15 alloantibodies, 46.7% had specificity to Rhesus blood group antigens, 40% to Kell and Lutheran blood group antigens, and 13.3% to Duffy blood group antigens. All the auto-antibodies reacted to Kell and Lutheran blood group antigens. The number of units transfused and the age of the patient were the two major risk factors found to be associated with development of alloantibodies. Difficulty in getting further blood for transfusion is the major consequence of alloimmunisation found in this study. To facilitate detection of antibodies to erythrocytes, it is recommended that, as a part the National blood transfusion policy, multiply transfused patients have extended red cell phenotyping before each subsequent transfusion; and Gel technology employed to replace the old manual technique in serological procedures.