Inhaled cerium oxide (CeO₂) nanoparticles have been shown to be capable of translocation to the liver where they can cause dose dependent toxic effects [1]. Herein, we investigate if the deposition of cerium in the liver is linked to increased oxidative stress and cellular apoptosis. Specific pathogen free male Sprague-Dawley rats were instilled with either vehicle (saline) or CeO₂ nanoparticles (7.0 mg/kg) and euthanized 1, 3, 14, 28, 56, or 90 days post exposure. Liver samples were evaluated for evidence of ceria deposition, oxidative stress and apoptosis. Inductively coupled plasma mass spectroscopy demonstrated that ceria deposition increased over time. Analysis of lipid peroxidation, superoxide levels and the number of TUNEL positive cells revealed evidence of increased oxidative stress and apoptosis at 1, 3 and 90 days post exposure. Immunoblotting showed that each of these time points were characterized by increases in the Bax/Bcl-2 ratio, elevations in caspase-9 protein levels and increases in caspase-3 protein expression. Interestingly, we found no evidence of oxidative stress or apoptosis at day 14, 28, or 56 post exposure. Taken together, these data demonstrate intratracheal instillation of CeO₂ nanoparticles is associated with increased liver ceria deposition, which causes biphasic oxidative stress and apoptotic response.