Titanium dioxide (TiO 2 ), a commercially important material, is used in a wide variety of products. Although TiO 2 is generally regarded as nontoxic, the cytotoxicity, pathogenicity, and carcinogenicity of TiO 2 nanoparticles have been recently recognized. The present study investigated TiO 2 nanoparticle-induced cell apoptosis and molecular mechanisms involved in this process in a mouse epidermal (JB6) cell line. Using the 3-(4,5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay, TiO 2 nanoparticles were found to exhibit higher cytotoxicity than fine particles. YO-PRO-1 iodide (YP) staining demonstrated that both TiO 2 nanoparticles and fine particles induced cell death through apoptosis. The signaling pathways involved in TiO 2 particle-induced apoptosis were investigated. Western-blot analysis showed an activation of caspase-8, Bid, BAX, and caspase-3 and a decrease of Bcl-2 in JB6 cells treated with TiO 2 particles. Time-dependent poly(ADP)ribose polymerase (PARP) cleavage induced by TiO 2 nanoparticles was observed. TiO 2 particles also induced cytochrome c release from mitochondria to cytosol. Further studies demonstrated that TiO 2 nanoparticles induced significant changes in mitochondrial membrane permeability, suggesting the involvement of mitochondria in the apoptotic process. In conclusion, evidence indicated that TiO 2 nanoparticles exhibit higher cytotoxicity and apoptotic induction compared to fine particles in JB6 cells. Caspase-8/Bid and mitochondrial signaling may play a major role in TiO 2 nanoparticle-induced apoptosis involving the intrinsic mitochondrial pathway. Unraveling the complex mechanisms associated with these events may provide further insights into TiO 2 nanoparticle-induced pathogenicity and potential to induce carcinogenicity.