Introduction: Sodium fluoride is commonly added to drinking water, tooth pastes and some mouth washes as decay preventive ingredient. However, it becomes toxic at long term exposure and leads to some adverse effects on various organs, including brain. Aim of the Work: Investigate the possible histological and immunohistochemical changes in the frontal cortex of sodium fluoride intoxicated rats and evaluate the possible protective role of vitamin E. Materials and Methods: Thirty-six adult male albino rats were used in this study and divided equally into three groups: control, treated and prophylactic. Treated group comprised animals that received a daily oral dose of sodium fluoride (20mg /kg) for 4 weeks. Prophylactic group received a daily oral dose of sodium fluoride (20 mg/kg) concomitant with vitamin E (400mg/kg) for the same duration. At the end of experiment, the frontal cortex of all rats was processed for light and electron microscopic examination. Immunohistochemical study was performed for detection of Glial Fibrillary Acidic Protein (GFAP) and Bcl-2. The obtained results were analyzed morphometrically and statistically. Results: Light microscopic examination of treated group revealed that most nerve cells in the cortical layers were distorted in shape with deeply stained shrunken nuclei. The ultrastructural study exhibited apoptotic neurons with heterochromatic nuclei. Their cytoplasm contained dilated and fragmented cisternae of rough endoplasmic reticulum. Immunohistohemical study of this group revealed intense positive immunoreaction for GFAP in the cytoplasm and processes of astrocytes while weak reaction for Bcl-2 was observed in most of nerve cells. The prophylactic group displayed normal appearance of most of nerve cells in the cortical layers and few cells appeared distorted. Positive immunoreaction for Bcl-2 was observed in many nerve cells and endothelium of blood vessels. Area percent of GFAP immunoreaction in astrocytes in all groups showed significant increase in the treated group when compared with the control or prophylactic groups. Conclusion: Chronic exposure to sodium fluoride results in histological and immunohistochemical changes on the neurons and glial tissue of frontal cortex. Furthermore, combined vitamin E supplementation has an ameliorating effect on these changes. So, dietary supplements of vitamin E may be beneficial for populations at risk