In this study, we examined whether rosiglitazone, a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, is neuroprotective in focal ischemic brain injury, and whether rosiglitazone can enhance the protective action of tissue plasminogen activator (tPA), an agent used clinically for thrombolytic therapy. Rats were subjected to ischemic brain injury by embolizing preformed clots into the middle cerebral artery (MCA). Treatment with rosiglitazone reduced infarction and improved functional recovery; it also enhanced the neuroprotective action of tPA and lengthened the time window for initiating tPA treatment. Occlusion of MCA resulted in a loss of collagen type IV, a major structural protein of the microvascular basal lamina, and tPA treatment worsened this loss. Rosiglitazone treatment prevented the reduction of collagen type IV in the ischemic injured brain by inhibiting the activation of matrix metallopeptidase-9 (MMP-9). In addition, rosiglitazone treatment reduced inflammatory reactions in the ischemic injured brain. Rosiglitazone either alone or in combination with tPA is an effective agent in the reduction of ischemic brain injury. The reduction of microvascular damage and inflammation contributes to the beneficial actions of rosiglitazone.