There are no data on long-term safety for the use of melatonin. Since Down syndrome children show low levels of melatonin, it is anticipated that exogenous treatment with melatonin could be caring.  The present study aimed to investigate the safety of melatonin treatment in Down syndrome children. The following children were recruited; children with Down syndrome, Children with down syndrome and treated with 1 mg/day melatonin and Down syndrome children treated with melatonin then melatonin was withdrawn for 18 months. Age matched ten healthy children attending for phlebotomy or day case procedures and whose results were subsequently normal. Biomarkers of liver functions, kidney function, and levels of cholesterol and triglycerides were estimated in serum.  After melatonin supplementation, there were insignificant changes in the levels of glutamic pyruvic transaminase (GPT), glutamic oxalacetic transaminase (GOT), creatinine, urea, cholesterol, triglycerides levels. In conclusion, the daily administration with melatonin for six months is safe on liver and kidney functions and the levels of cholesterol, triglycerides.