BACKGROUND: Down syndrome (DS) is a complex genetic disease. Some clinical features of patients with this syndrome could be related to functional folate deficiency. The purpose of this study was to evaluate the total homocysteine (T-Hcy) metabolism in DS children and to determine whether the supplementation with folic acid therapy would shift the genetically induced metabolic imbalance or not. METHODS: Thirty-five infants with DS, with the mean age of 17.66 ± 12.24 months were included in this study. They were selected from those attending the Genetic Outpatients Clinic in Children hospital. RESULTS: Our results revealed that Down syndrome children had a significant decrease in serum plasma T-Hcy level after the treatment with folic acid [11.79 ± 0.92 vs. 14.41 ± 4.93 μmol/L]. A significant negative correlation was found between T-Hcy and folic acid serum levels [r = -0.112; P<0.05].CONCLUSIONS: We concluded that the regulation of methylation pathways in Down syndrome patients becomes important in the light of possible normalization of the metabolic imbalance and the detection of increased sensitivity to therapeutic interventions. KEY WORDS: Down syndrome, hyperhomocysteine, folic acid, vitamin B-12.