The function of peroxisome proliferator-activated receptor-γ (PPARγ) in hepatic inflammation and injury is unclear. In this study, we sought to determine the role of PPARγ in hepatic ischemia/reperfusion injury in mice. Male mice were subjected to 90 minutes of partial hepatic ischemia followed by up to 8 hours of reperfusion. PPARγ was found to be constitutively activated in hepatocytes but not in nonparenchymal cells. Upon induction of ischemia, hepatic PPARγ activation rapidly decreased and remained suppressed throughout the 8-hour reperfusion period. This reduced activation was not a result of decreased protein availability as hepatic nuclear PPARγ, retinoid X receptor-α (RXRα), and PPARγ/RXRα heterodimer expression was maintained. Accompanying the decrease in PPARγ activation was a decrease in the expression of the natural ligand 15-deoxy-Delta12,14-prostaglandin J2. This was associated with reduced interaction of PPARγ and the coactivator, p300. To determine whether PPARγ activation is hepatoprotective during hepatic ischemia/reperfusion injury, mice were treated with the PPARγ agonists, rosiglitazone and connecting peptide. These treatments increased PPARγ activation and reduced liver injury compared to untreated mice. Furthermore, PPARγ-deficient mice had more liver injury after ischemia/reperfusion than their wild-type counterparts. Conclusion: These data suggest that PPARγ is an important endogenous regulator of, and potential therapeutic target for, ischemic liver injury. (HEPATOLOGY 2007.)