The present study investigated the penetration and potential toxicity of titanium dioxide (TiO(2)) nanoparticles following its dermal exposure in vitro and in vivo. In vitro, after exposure to isolated porcine skin for 24h, titanium dioxide nanoparticles of carious sizes cannot penetrate through stratum corneum. Interestingly, when studied in vivo, quite different results were obtained. After topically applied on pig ear for 30 days, TiO(2) nanomaterials (4 nm and 60 nm) can penetrate through horny layer, and be located in deep layer of epidermis. Furthermore, after 60 days dermal exposure in hairless mice, nano-TiO(2) particles can penetrate through the skin, reach different tissues and induce diverse pathological lesions in several major organs. Notably, P25 (21 nm) TiO(2) nanomaterials shows a wider tissue distribution, and can even be found in the brain without inducing any pathological changes. Among all of the organs examined, the skin and liver displayed the most severe pathological changes that correspond to the significant changes in SOD and MDA levels. These results suggest that the pathological lesions are likely to be mediated through the oxidative stress induced by the deposited nanoparticles. Accordingly, the collagen content expressed as HYP content are also significantly reduced in mouse skin samples, indicating that topically applied nano-TiO(2) in skin for a prolonged time can induce skin aging. Altogether, the present study indicates that nanosize TiO(2) may pose a health risk to human after dermal exposure over a relative long time period.