Some recent studies have been previously suggested that nanoparticulate titanium dioxide (TiO) damaged liver function and decreased immunity of mice, but the spleen injury and its oxidative stress mechanism are still unclear. To understand the spleen injury induced by intragastric administration of nanoparticulate anatase TiO for consecutive 30 days, the spleen pathological changes, the oxidative stress, and p38 and c-Jun N-terminal kinase signaling pathways, along with nuclear factor-κB and nuclear factor-E2-related factor-2 (Nrf-2), were investigated as the upstream events of oxidative stress in the mouse spleen from exposure to nanoparticulate TiO . The results suggested that nanoparticulate TiO caused congestion and lymph nodule proliferation of spleen tissue, which might exert its toxicity through oxidative stress, as it caused significant increases in the mouse spleen reactive oxygen species accumulations, subsequently leading to the strong lipid peroxidation and the significant expression of heme oxygenase-1 via the p38-Nrf-2 signaling pathway. The studies on the mechanism by which nanoparticulate TiO induced the p38-Nrf-2 signaling pathway are helpful to a better understanding of the nanoparticulate TiO-induced oxidative stress and reduction of immune capacity. © 2010 Springer Science+Business Media, LLC.