BACKGROUND: ECHS1 is a key enzyme of the valine catabolic pathway and oxidation of fatty acids. In ECHS1 deficiency (ECHS1D), accumulation of toxic intermediates from the valine induces neurodegeneration, which presents Leigh syndrome (LS). Therefore, valine restriction is suggested as an effective therapy. Further, cysteamine may detoxify the toxic metabolites themselves and N-acetylcysteine (NAC) is a potent antioxidant preventing neurological affect. Herein, we report the therapeutic effects of dietary therapy, cysteamine, and NAC in two siblings with ECHS1D, including their clinical, neuroradiological, and chemical aspects. CASE REPORT: The elder sister was the proband and was diagnosed as LS at 13 months of age. Gene analysis identified compound heterozygous ECHS1 mutations. Her psychomotor development was regressed, and she became bedridden. At 4 years old she started a low protein diet (LPD), but with no obvious neurological change. The younger brother was confirmed early with ECHS1D and received cysteamine and NAC treatment from 5 months of age, which could not prevent him developing LS at 7 months of age. Thus, we started a LPD at 14 months of age, with which he regained his ability to roll over, then we proceeded to a valine-restricted diet. The brain magnetic resonance image hyperintensity was diminished, and the lactate peak on magnetic resonance spectroscopy decreased. His neurological outcome is better than his elder sister. In both cases, excretion of valine metabolites decreased after dietary therapy without obvious adverse effects. CONCLUSION: Early initiation of dietary therapy may reduce neurological sequelae in patients with ECHS1D.