Stroke is a devastating disease with limited treatment options. Recently, we found that the peroxisome proliferator-activated receptor-γ (PPARγ) agonists troglitazone and pioglitazone reduce injury and inflammation in a rat model of transient cerebral ischemia. The mechanism of this protection is unclear, as these agents can act through PPAR-γ activation or through PPAR-γ-independent mechanisms. Therefore, we examined PPAR-γ expression, DNA binding and transcriptional activity following stroke. In addition, we used a PPAR-γ antagonist, T0070907, to determine the role of PPAR-γ during ischemia. Using immunohistochemical techniques and real-time PCR, we found low levels of PPAR-γ mRNA and PPAR-γ immunoreactivity in nonischemic brain; however, PPAR-γ expression dramatically increased in ischemic neurons, peaking 24 h following middle cerebral artery occlusion. Interestingly, we found that in both vehicle- and agonist-treated brains, DNA binding was reduced in the ischemic hemisphere relative to the contralateral hemisphere. Expression of a PPAR-γ target gene, lipoprotein lipase, was also reduced in ischemic relative to nonischemic brain. Both DNA binding and lipoprotein lipase expression were increased by the addition of the PPAR-γ agonist rosiglitazone. Finally, we found that rosiglitazone-mediated protection after stroke was reversed by the PPAR-γ antagonist T0070907. Interestingly, infarction size was also increased by T0070907 in the absence of PPAR-γ agonist, suggesting that endogenous PPAR-γ ligands may mitigate the effects of cerebral ischemia.