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Background and Objective: In pathogenesis of beta major thalassemia, tissue damage is occurring due to oxidative stress. The present study was designed to evaluate the effects of vitamin E supplementation on serum Paraoxonase, SOD, GPX enzyme activity and lipid profiles in beta major thalassemia patients. Materials and Methods: In this clinical tiral study, Sixty (25 males, 35 females) beta major thalassemia patients with age≥18 years who had criterias to enter the study, were selected randomely in two groups. The patients in interventional group, vitamin E at a dose of 400 mg/day were given for three months, with no supplementations in control group. The enzyme activities of paraoxonase, SOD, GPX and lipid profiles (LDL-c, HDL-c, triglyceride, total Antixidant Capacity) were measured prior and after 3 months in both case and control groups. Data analyzed by using paired t-test. Results: Significant increases in serum levels of vitamin E, Paraoxonase activity, HDL cholesterol (P<0.001), BMI (P≤0.001) and a significant reduction in GPX activity (P<0.05) were observed in cases compared to controls. Conclusion: The vitamin E supplementation may be useful in reducing oxidative stress and lipid profiles in beta major thalassemic patients.