BACKGROUND Beta-thalassemia causes a severe hemolytic anemia in patients necessitating frequent transfusions leading to iron overload and endocrine complications, especially diabetes mellitus. We tried to determine the change or effect on carbohydrate physiology and oxidation markers and the association of these markers in chronic transfusion-dependent beta-thalassemia major and beta-thalassemia/HbE (beta-TM) patients. METHODS Prospective study on 60 beta-TM patients, receiving only regular blood transfusions, and 20 healthy controls were enrolled for oral glucose tolerance test, fasting insulin, Homeostasis Model Assessment of insulin resistance (HOMA-IR), liver function test, iron overload, oxidative stress, and lipid profile at baseline. The same tests were repeated after 6 months. RESULTS One beta-TM patient had impaired glucose tolerance. Fasting glucose, insulin, ferritin, MDA, TG concentrations, HOMA-IR, and liver profiles were significantly higher while Hb, Hct, TC, HDL-C, LDL-C concentrations and TAC were significantly lower in beta-TM patients than controls (p < 0.001). Fasting glucose, HOMA-IR and beta-cell function were significantly correlated with MDA and glucose, AST, ALT, MDA were significantly correlated with ferritin (p < 0.05). Multiple forward stepwise linear regression analyses of the significant variables showed that in these beta-TM patients, independent predictors of HOMA-IR were fasting glucose (beta = 0.634, r2 = 0.374, p < 0.001), HDL-C (beta = 0.249, r2 = 0.418, p = 0.043) and MDA (beta = 0.225, r2 = 0.466, p = 0.029). CONCLUSIONS Progression of iron overload, oxidative stress and hyperinsulinemia were substantially and persistently higher in beta-TM patients. We observed a positive association between oxidative stress, iron overload and insulin resistance in these beta-TM patients.