Thiazolidinediones (TZDs) are potent synthetic agonists of the ligand-activated transcription factor peroxisome proliferatoractivated receptor-␥ (PPAR␥). TZDs were shown to induce neuroprotection after cerebral ischemia by blocking inflammation. As spinal cord injury (SCI) induces massive inflammation that precipitates secondary neuronal death, we currently analyzed the therapeutic efficacy of TZDs pioglitazone and rosiglitazone after SCI in adult rats. Both pioglitazone and rosiglitazone (1.5 mg/kg i.p.; four doses at 5 min and 12, 24, and 48 h) significantly decreased the lesion size (by 57 to 68%, p Ͻ 0.05), motor neuron loss (by 3-to 10-fold, p Ͻ 0.05), myelin loss (by 66 to 75%, p Ͻ 0.05), astrogliosis (by 46 to 61%, p Ͻ 0.05), and microglial activation (by 59 to 78%, p Ͻ 0.05) after SCI. TZDs significantly enhanced the motor function recovery (at 7 days after SCI, the motor scores were 37 to 45% higher in the TZD groups over the vehicle group; p Ͻ 0.05), but the treatment was effective only when the first injection was given by 2 h after SCI. At 28 days after SCI, chronic thermal hyperalgesia was decreased significantly (by 31 to 39%; p Ͻ 0.05) in the pioglitazone group compared with the vehicle group. At 6 h after SCI, the pioglitazone group showed significantly less induction of inflammatory genes [interleukin (IL)-6 by 83%, IL-1␤ by 87%, monocyte chemoattractant protein-1 by 75%, intracellular adhesion molecule-1 by 84%, and early growth response-1 by 67%] compared with the vehicle group (p Ͻ 0.05 in all cases). Pioglitazone also significantly enhanced the post-SCI induction of neuroprotective heat shock proteins and antioxidant enzymes. Pretreatment with a PPAR␥ antagonist, 2-chloro-5-nitro-N-phenyl-benzamide (GW9662), prevented the neuroprotection induced by pioglitazone.Peroxisome proliferator-activated receptor (PPAR) and retinoid X receptor are ligand-activated transcription factors of the nuclear hormone receptor superfamily. Upon ligand binding, PPAR forms a heterodimeric complex with retinoid X receptor that binds to the cis-acting sequences (peroxisome proliferator response element) on DNA to initiate or repress the transcription of target genes (Blanquart et al., 2003). PPAR exists as three isoforms (␣, ␥, and ␦/␤) that control many cellular functions including lipid metabolism, glucose absorption, and cell growth and differentiation (Escher and Wahli, 2000). 15-Deoxy-⌬-12,14-prostaglandin J 2 (15-d-PGJ 2 ) is the natural agonist and thiazolidinediones (TZDs) (troglitazone, ciglitazone, rosiglitazone, and pioglitazone) are potent synthetic agonists of PPAR␥. Of these, troglitazone was removed from the market because of hepatotoxicity, whereas rosiglitazone and pioglitazone are currently ap-