Background Titanium dioxide nanoparticles (TiO2 NPs) are used extensively in many commercial products, including paints, cosmetics, plastics, paper, and food. Therefore, potential widespread exposure may occur during both manufacturing and application. Their potential risk for central nervous system has elicited much concern recently. Aim of the work The aim of this work was to evaluate the toxicity of TiO2 NPs on cerebral cortex of adult male albino rats. Material and Methods Thirty adult male albino rats were divided equally into three groups. Group I served as control, group II in which animals received low dose of TiO2 (600 mg/ Kg/day for 5 consecutive days) and group III in which animals received high dose of TiO2 (1 g/ Kg/day for 5 consecutive days). After 4 weeks from the last dose, rats were sacrificed and posterior parietal lobe of cerebral cortex was processed and examined using histological and immunohistochemical techniques. Results The results revealed that a low dose of TiO2 induced minimal histological changes. Few pyramidal cells showed darkly stained hyperchromatic nuclei. The high dose TiO2 group showed marked histological changes in pyramidal cells; some cells appeared with deeply stained nuclei, with significant increase (P≤0.05) in caspase-3 reaction compared with control group. EM revealed electron-lucent vacuoles in cytoplasm, disrupted mitochondria and dilated cisterns of rough endoplasmic reticulum. Conclusion High doses of TiO2 NPs should be avoided due to its cerebral cortex toxicity in rats.