Background: Beta-thalassemia is an inherited haemoglobin disorder that is common in the Middle East and Africa. Various studies have attributed the increased susceptibility to bacterial infections in beta-thalassemia patients to changes in their immunological status. This study aimed to evaluate changes in the functions of the immune system in pediatric patients with β-thalassemia major. Methods:We conducted this case-control study in the Pediatric Haematology Outpatient Department in collaboration with the Department of Clinical Pathology of the Faculty of Medicine, Zagazig University, on 56 patients divided into two groups. The case group included 28 children in whom β-thalassemia major was diagnosed, and the control group consisted of 28 healthy children of the same age and sex. All the children underwent complete blood analysis, immunophenotypic analysis of peripheral blood lymphocyte subsets, assessment of serum immunoglobulin levels, complement 3 (C3) and complement hemolysis activity (CH50) using enzyme-linked immunosorbent assays (ELISAs). Results:The total white blood cell (WBC), lymphocyte and neutrophil count were significantly higher in the patient group than in the control group. CD19+ expression on lymphocytes,CD3+, CD4+ and CD8+ Tcell subsets were significantly higher in patients than in controls with significant increases in the levels of immunoglobulins, including IgG, IgM, IgA and total IgE. The natural killer cell and C3 levels were significantly lower in the patients than in the controls. CH50 showed a diagnostic accuracy of 64.3%, with a CH50 value of 88.1 pg/ml. Conclusions: This study demonstrated significant derangements in adaptive and innate immune systems in children with beta-thalassemia major.