Background: Increased oxidative damage is well known in chronic hemoglobinopathies due to increased resting oxygen consumption and circulating pro-oxidative free hemoglobin. But it is still unknown whether the level of antioxidants like vitamin E level and selenium differ in beta thalassemia and sickle cell anemia or contribute to differences in the severity of oxidative damage in these two diseases. Objective: The present study was carried out to investigate the antioxidants (vitamin E and selenium) and lipid profile in transfusion dependant Egyptian children with beta thalassemia and sickle cell anemia and to examine whether these variables differ in these two diseases or correlate with iron overload status or transfusion requirements. Materials and Methods: A case-control study conducted at University Children’s’ Hospital, Faculty of Medicine, Cairo University, Egypt. We measured the serum levels of vitamin E, selenium and Lipid profile (cholestrol, HDL, LDL, TG) in 60 transfusion dependent children with beta thalassemia and sikle cell anemia in a steady state aged from 6 to 18 years and 30 apparently healthy age/sex matched controls. Results: β-Thalassemia group showed significantly higher mean transfusion frequency when compared to SCD group (p=0.005). LDH was nearly five times larger than normal values and C-reactive protein (CRP) was also almost 3-fold larger in SCD patients and SCD patients showed statistically significantly higher values of LDH and CRP when compared to TM group (p<0.05). Thirteen percent TM patients exhibited abnormal values of AST and ALT exceeding 2 folds versus none of SCD group. All TM and SCD cases had below normal Selenium level versus 11 (36.7%) of the control group, and mean Selenium level was comparable between Thalassemia and SCD groups (p>0.05) and both groups showed significantly lower levels when compared to the control group (p<0.05). Similarly, all TM and SCD cases had below normal vitamin E level vs. none of the control group, and mean vitamin E level was comparable between TM and SCD cases (p>0.05) and both groups had significantly lower levels when compared to the control group (p<0.05). Total cholesterol, LDL-cholesterol, as well as TG were comparable in patients with TM and SCD (p>0.05) and all were significantly lower than relevant controls (p<0.05). However, there was no significant differences between mean HDL- cholesterol levels in the three groups (p>0.05). Among TM group; serum ferritin and selenium levels didn't correlate with any of the tested variables including other antioxidants. Levels of vitamin E were proportionally correlated with ALT values (r = 0.4; P = 0.049) and AST (r = 4; P = 0.039), however, no other clear correlation was found between vitamin E and other variables. Transfusion rate correlated positively with CRP (r=0.341, p=0.065), AST correlated inversely with TG (r=-0.389, p=0.034) and Retics correlated negatively with Hb (r=-0368, p=0.046) and positively with ALT (r=0.424, p=0.020). Among SCD cases, serum ferritin, selenium and vitamin E levels didn't correlate with any of the tested variables. Conclusion: These results demonstrate that children with TM and SCD have increased oxidative stress and depleted antioxidants relative to healthy controls. However, levels of these antioxidants did not correlate with indices of iron overload, hemolysis, or inflammation in chronically transfused TM and SCD patients.