Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a nuclear membrane-associated transcription factor that governs the expression of various inflammatory genes. PPAR-gamma agonists protect peripheral organs from ischemic injury. In the present study, we investigated whether the PPAR-gamma agonist rosiglitazone is neuroprotective against focal ischemic brain injury. C57/B6 mice underwent 1.5-h middle cerebral artery occlusion, and received either vehicle or rosiglitazone treatment of 0.75, 1.5, 3, 6 or 12 mg/kg (n = 9 per group). Cerebral infarct volume, neurological function, expression of pro-inflammatory proteins and neutrophil accumulation were assessed after ischemia and reperfusion. At 48 h after ischemia, infarct volume was significantly decreased with 3-12 mg/kg of rosiglitazone, with a time window of efficacy of 2 h after ischemia at the optimal dose (6 mg/kg). Neutrophil accumulation was significantly decreased in the brain parenchyma of rosiglitazone-treated mice. Ischemia-induced expression of several inflammatory cytokines and chemokines was markedly reduced in rosiglitazone-treated brains, as determined using proteomic-array analysis. Rosiglitazone treatment improved neurological function at 7 days after ischemia. Moreover, in cultured cortical primary microglia, rosiglitazone attenuated inflammatory responses by decreasing lipopolysaccharide-induced release of tumor necrosis factor-alpha, interleukin (IL)-1beta and IL-6. These results suggest that the PPAR-gamma agonist rosiglitazone has neuroprotective properties that are at least partially mediated via anti-inflammatory actions, and is thus a potential novel therapeutic agent for stroke.