Objective: The usage of Titanium Dioxide NanoParticles (TiO2NPs) on a large scale of applications was a reason of a variety of many health problems. The aim of the current study was to evaluate the immune toxic effects of short term administration of TiO2NPs on spleen. Material and Methods: Forty Adult male Rats were equally divided into four groups as follows: Group I: negative control, Group II: positive control, Group III: received TiO2NPs (1200 mg/kg) orally daily for 12 weeks. Group IV: follow up group received TiO2NPs by the same dose, route and for the same duration as TiO2NPs group and then they were left untreated for another 8 weeks. Total leukocytes, differential leukocytic counts, Interleukins IL-2 and IL-10 levels were measured, the spleen sections were examined immunohistochemically for the detection of CD4+ and iNOS expressing cells. Histopathological alterations in the spleen were also evaluated. Moreover, DNA damage was evaluated by comet assay. The results: TiO2NPs exposure for 12 weeks resulted in significant decreased in the total and deferential leukocytic counts, serum interleukins IL-2 as well as IL-10. It caused marked decrease in CD4+T-lymphocytes and increase in iNOS expressing cells indicating oxidative stress in spleen tissues. It also caused histopathological disruption of spleen architecture and produced DNA damage in splenocytes. Discontinuation of TiO2NPs administration for 8 weeks resulted in significant improvement of leukocytes, interleukins, increase in CD4+ T-lymphocytes and decrease in iNOS expressing cells in spleen tissues. Moreover, there was moderate improvement in histopathological alterations and DNA damage. Conclusion:TiO2NPs consumption have immunotoxic effects which may resulted from genetic damage and oxidative stress in the spleen of adult male albino rats which could be improved by its discontinuation for a period of time and it was recommended to increase the period of discontinuation as complete improvement may occur