Cerium oxide nanoparticles have oxygen defects in their lattice structure that enables them to act as a regenerative free radical scavenger in a physiological environment. We performed a comprehensive in vivo analysis of the biological distribution and antioxidant capabilities of nanoceria administered to mice perorally (PO), intravenously (IV), or intraperitoneally (IP) by dosing animals weekly for 2 or 5 weeks with 0.5 mg kg(-1) nanoceria. Next, we examined if nanoceria administration would decrease ROS production in mice treated with carbon tetrachloride (CCl(4)). Our results showed that the most extensive and cumulative nano-deposition was via IV and IP administered while PO administration showed mice excreted greater than 95% of their nanoceria within 24 h. Organ deposition for IV and IP mice was greatest in the spleen followed by the liver, lungs, and kidneys. Elimination for all administration routes was through feces. Nanoceria administration showed no overt toxicity, however, WBC counts were elevated with IV and IP administration. Our in vivo studies show that nanoceria administration to mice with induced liver toxicity (by CCl(4)) showed similar findings to mice treated with N-acetyl cystine (NAC), a common therapeutic to reduce oxidative stress. Taken together, our studies show that nanoceria remains deposited in tissues and may decrease ROS, thereby suggesting that cerium oxide nanoparticles may be a useful antioxidant treatment for oxidative stress.