Titanium-dioxide nanoparticles (TNP) are used in various consumable goods. Evidence has demonstrated the cytotoxicity of TNPs, but exact mechanism is yet to be elucidated. The present study has been aimed at finding out the mechanism of TNP-induced toxicity in biological system. Different doses of anatase-TNPs administrated intravenously to Wistar rats for once a week for 1 month and properties of T-H cells, macrophages, cytokines secretion, oxidative damage, apoptotic pathway, and hematological and pathological changes were investigated as downstream events of TNP-mediated cytotoxicity. Result suggests that TNPs induce T-H1 and T-H2 response as measured by immunophenotyping (interferon gamma (IFN-gamma) and interleukin (IL)-4) of T-H cells, causing induction of M1 (nitric oxide (NO), nitric oxide synthase (iNOS), NF-kappaB (NF-kappa B), cyclooxygenase-2 (COX-2), IL-1, IL-6, and TNF-alpha) and M2 (Arg-1, Ym1) macrophages response. At lower dose, T-H1 or M1 response counteracted by T-H2 or M2 response, resulting in insignificant oxidative damage. However, with increasing dose of TNPs, the M1 response was increased over M2 response resulting in significant tissue damage. The M1-induced inflammatory response was found to cause DNA and chromosomal damage resulting apoptosis induction via upregulation of Bax/Bcl-2 ratio and subsequent loss of mitochondrial membrane potential and cyto c release in splenocytes. The TNP-led inflammatory response also causes damage at different tissue levels.