BACKGROUND: Intra-abdominal infection or peritonitis is a cause for great concern due to high mortality rates. The prognosis of severe intra-abdominal infection is significantly diminished in the presence of acute kidney injury (AKI) which is often characterized by renal tubular cell death that can lead to renal failure. The purpose of the current study is to examine the therapeutic efficacy of cerium oxide (CeO2) nanoparticles for the treatment of peritonitis-induced AKI by polymicrobial insult. RESULTS: A one-time administration of CeO2 nanoparticles (0.5 mg/kg) in the absence of antibiotics or other supportive care, attenuated peritonitis-induced tubular dilatation and the loss of brush border in male Sprague-Dawley rats. These improvements in renal structure were accompanied by decreases in serum cystatin-C levels, reduced renal oxidative stress, diminished Stat-3 phosphorylation and an attenuation of caspase-3 cleavage suggesting that the nanoparticle treatment improved renal glomerular filtration rate, diminished renal inflammation and reduced renal apoptosis. Consistent with these data, further analysis demonstrated that the CeO2 nanoparticle treatment diminished peritonitis-induced increases in serum kidney injury molecule-1 (KIM-1), osteopontin, ß-2 microglobulin and vascular endothelial growth factor-A (VEGF-A) levels. In addition, the nanoparticle attenuated peritonitis-induced hyperglycemia along with increases in blood urea nitrogen (BUN), serum potassium and sodium. CONCLUSION: CeO2 nanoparticles scavenge reactive oxygen species and attenuate polymicrobial insult induced increase in inflammatory mediators and subsequent AKI. Taken together, the data indicate that CeO2 nanoparticles may be useful as an alternative therapeutic agent or in conjunction with standard medical care for the treatment of peritonitis induced acute kidney injury.