Background: Experimental data indicate that excessive production of reactive oxygen molecules contributes to progressive renal injury and that treatment with antioxidants may attenuate this damage. Several studies indicate the pathophysiological importance of reactive oxygen species in patients with nephrotic syndrome. Objectives: To test the hypothesis that oxygen free radicals are mediators of excessive protein permeability in steroid resistant nephrotic syndrome (SRNS) and to assess the therapeutic effect of vitamin E (VE) supplementation as antioxidant on the level of proteinuria in those children. Methods:  The present study included 26 patients with SRNS, subdivided into 2 equal groups and 15 matched healthy children as controls. Patients in group I received standard therapy of methylprednisone and cyclophosphamide plus VE (200 IU twice a day by mouth) for 4 months, group II patients received the standard medical treatment protein: creatinine ratio (mg/mg) in an early morning specimen of urine was determined in all studied children at the beginning  and at follow-up. Erythrocyte and plasma glutathione peroxidase (GSH-Px) and erythrocyte superoxide dismutase (SOD) activities, and erythrocyte and plasma levels of malondialdehyde (MDA) were measured as oxidative stress indices. Results: Initially patients in both groups showed significantly lower activities of erythrocyte GSH-Px (14.2 ± 2.2 & 16.5 ± 4.5 U/gHb) and plasma GSH-Px (143.56 ± 20.3 & 169.25 ± 25.4 U/L) in comparison to controls (24.34 ± 2.5 U/gHb & 278.43 ± 37.34 U/L respectively) [p ˂ 0.01 for each]. They also had significantly lower erythrocyte SOD activities (1484.24 ± 228.13 & 1373.54 ± 265.53 U/gHb) than that of the controls (2004.53 ±       229.72 U/gHb) [p ˂ 0.01]. There were significant increases in the levels of MDA of both erythrocytes (346.5 ± 32.5 & 312.6 ± 29.7 nmol/gHb) and plasma (5.6 ± 1.5 & 4.9 ± 1.3 nmol/ml) of patients in the two groups compared with the controls (189.5 ± 24.2 nmol/gHb & 1.52 ± 0.2 nmol/ml respectively) [p ˂ 0.001 for each ]. After 4 months patients who received VE supplementation showed significant reduction in protein: creatinine ratio from 9.25 ± 3.16 to 3.75 ± 1.3 (p ˂ 0.01) and significant correction of oxidative stress indices as evident by significant decrease in MDA level with concomintant increase in the activities of the antioxidants  GSH-Px & SOD . However patients in group II showed no evidence of such significant improvement. Conclusions: The results obtained indicate an abnormality in the antioxidative system of children with SRNS and oral administration of VE to children with SRNS leads to significant reduction in proteinuria. Thus, VE may be a useful adjunct in treating children with SRNS.