Down syndrome (DS) is a chromosome abnormality with specific clinical symptoms and mental deficiencies caused by trisomy of chromosome 21. Although the genetic changes cannot be cured, control of the associated symptoms may improve the patients’ quality of life. Evidences indicate oxidative stress may play a role in some of the degenerative changes seen in DS. The present study aimed to evaluate red blood cell antioxidant capacity and redox cycle enzymes activities before and after nutritional supplementation, in an attempt to protect DS children from premature degeneration. The study included 21 children with DS, their age ranged from 1 month to 5 years received mixture of nutritional supplements (formula X) for six months and 20healthy matched children served as controls received placebo. Reduced glutathione (GSH), in addition to antioxidant enzymes activities[superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), glutathione reductase (GR), and the glutathione-Stransferase (GST)] were assessed to all participants. Before nutritional supplementation, GSH and GST levels were significantly low, while SOD levels in DS children were significantly high compared to controls. After 6 months' supplementation, significant high levels were observed in the activity of GPx and CAT with elevated GPx/GR ratio and reduced SOD/(CAT + GPx) ratio among DS children. Supplementation of DS children with formula X is important at early years of life, as it may protect against harmful oxidative damage.