Hydrocephalus is a disabling disease for children, but current data concerning the effects of melatonin on ventricular enlargement are still limited. We have investigated the changes in the choroid plexuses (CPs) of ventricles and blood-brain barrier (BBB) of hydrocephalic rats. Forty-five Swiss Albino rats at age 2 weeks were divided into three equal groups: control, hydrocephalus, and melatonin-treated hydrocephalus groups. Hydrocephalus was induced by kaolin injection into the cisterna magna of all pups except control group and melatonin was given at a daily dose of 0.5 mg/100 g body weight for 4 weeks. At the end of the study, one animal from each group was examined using a gamma camera to study the disruption of BBB due to hydrocephalus. All animals were then killed for assay of glutathione (GSH) and nitric oxide (NO), as well as histological study of the CPs during the hydrocephalus. We observed an increased BBB activity was found in hydrocephalus group, while melatonin reversed these changes. It was found that NO concentration was elevated in hydrocephalus group and melatonin partly abolished the increased levels of NO. In contrast, GSH levels were significantly decreased in hydrocephalus group, while melatonin increased the tissue GSH level (p<0.01). Histologically, there was a significant alteration in the CPs of the ventricles of hydrocephalic animals, but it was regressed after melatonin treatment in consistent with the gross morphological changes related to hydrocephalus. In conclusion, our results clearly demonstrated for the first time the neuroprotective effects of melatonin upon hydrocephalus-induced CP changes in infantile rats, but further studies are needed to suggest melatonin as a candidate protective drug in children.