Peroxisome proliferator-activated receptor-alpha (PPARalpha) has been suggested to protect against chemically induced hepatobiliary injuries in rodents. This function could mask the potential toxicities of perfluorooctanoic acid (PFOA) that is an emerging environmental contaminant and a weak ligand of PPARalpha. However its function has not been clarified. In this study, PFOA was found to elicit hepatocyte and bile duct injuries in Pparalpha-null mice after 4 wk treatment with PFOA ammonium salt (0, 12.5, 25, 50 micromol/kg/d, gavage). In wild-type mice, PFOA caused major hepatocellular damage dose-dependently and minor cholangiopathy observed only at 25 and 50 micromol/kg. In treated Pparalpha-null mice, PFOA produced marked fat accumulation, severe cholangiopathy, hepatocellular damage and apoptotic cells especially in bile ducts. Oxidative stress was also increased 4-fold at 50 micromol/kg and TNF-alpha mRNA was upregulated more than 3-fold at 25 micromol/kg in Pparalpha-null mice. Biliary bile acid/phospholipid ratios were higher in Pparalpha-null mice than in wild-type mice. Results from these studies suggest that PPARalpha is protective against PFOA and have a critical role in drug induced hepatobiliary injury.