Background: Melatonin has been shown to reduce hypertension, protect the ischemic/reperfused heart and decelerate the process of atherosclerosis but the effects of melatonin levels in children with congenital heart disease suffering from heart failure (HF) are not well understood. This study aimed to assess outcome of serum levels of melatonin in children with congenital heart disease suffering from heart failure. Methods: This case-control study was conducted at Pediatric Department, Faculty of Medicine, Zagazig University on 40 patients. Case group included children with congenital heart disease suffering from HF; control group of apparently healthy children matched by age & sex. Patients with ROSS score of >2 points were included in the study and divided into three groups according to severity of heart failure: mild (score:3-6), moderate (score:7-9), and severe (score: 10-12). Results: children with congestive heart failure had significantly higher serum melatonin level than control children. Receiver operating characteristic (ROC) curve analysis revealed that serum melatonin can differentiate between children with Congestive heart failure (CHF) and healthy controls with an area under the curve (AUC) of 1.0 for serum melatonin with an excellent discrimination ability with optimal sensitivity, specificity, and positive predictive value. Conclusions: Serum melatonin levels play a protective role in children with severe heart failure. It is likely that increasing melatonin levels may act as a compensatory mechanism in pediatric children with CHD with heart failure. We concluded that serum melatonin is a potential prognostic and excellent diagnostic biomarker in children with CHF.