A proteomic analysis of the proteins in mouse brain that were differentially expressed in response to $TiO_2$ nanoparticles was conducted to better understand the molecular mechanism of $TiO_2$ nanoparticle-induced brain toxicity at the protein level. A total of 990 proteins from mouse brain were resolved by two-dimensional gel electrophoresis. A comparative proteomic analysis revealed that the expression levels of 11 proteins were changed by more than 2-fold in response to $TiO_2$ nanoparticles: eight proteins were upregulated and three were downregulated by $TiO_2$ nanoparticles. In addition, the activities of several antioxidative enzymes and acetylcholine esterase were reduced in $TiO_2$ nanoparticle-exposed mouse brain. The protein profile alterations seem to be due to an indirect effect of $TiO_2$ nanoparticles, because $TiO_2$ nanoparticles were not detected in the brain in this investigation.