Background: Titanium dioxide (TiO2) is a white pigment that can be used in paints, coatings, plastics, papers, inks, medicines, pharmaceuticals, food products, cosmetics, and toothpaste. Titanium dioxide nanoparticles (TiO2 NPs) have been reported to elicit various adverse cellular effects including oxidative stress and DNA damage. N-acetylcysteine (NAC) is an antioxidant and free radical scavenger used to combat oxidative stress-induced damage in various tissues. Aim of the Work: is to study the toxic effects of TiO2 NPs oral administration and the protective role of NAC on the immune system of adult male albino rats. Thirty adult male albino rats were divided into 4 groups: Group I subdivided into: Subgroup (A): negative control. Subgroup (B): positive control received 1 ml of 5% gum acacia solution by oral gavage once daily. Group II: gavaged orally 100 mg/kg NAC once daily. Group III: gavaged orally 1200 mg/kg titanium dioxide nanoparticles (1/10 LD 50) in 1ml of 5% gum acacia solution as a solvent once daily. Group IV: gavaged orally (100 mg/kg NAC then 1200 mg/kg TiO2 NPs once daily. After 6 weeks rats from each group and subgroup were subjected the following biochemical parameters: Tumor necrosis factor alpha and CBC with differential count. The rats were sacrificed and spleen was dissected and subjected to histopathological examination. Cell suspension from the spleen was examined to determine the extent of DNA damage through DNA extraction and gel electrophoresis. Conclusion: TiO2 NPs induced time dependent toxic effects and DNA damage in the spleen and administration of NAC with TiO2 NPs offers protection against their damaging effect. Recommendation: it is recommended to increase public awareness about health impact of TiO2 nanoparticles through nonessential drug additives, food colors, toothpastes etc.to limit their ingestion.