Inflammatory and ischemic processes contribute to the development of secondary brain damage after mechanical brain injury. Recent data suggest that thiazolidinediones (TZDs), a class of drugs approved for the treatment of non-insulin-dependent diabetes mellitus, effectively reduces inflammation and brain lesion by stimulation of the peroxisome proliferator-activated receptor-γ (PPAR-γ). The present study investigates the influence of the TZD pioglitazone and rosiglitazone on inflammation and secondary brain damage after experimental traumatic brain injury (TBI). A controlled cortical impact (CCI) injury was induced in male C57BL/6 mice to investigate following endpoints: (1) mRNA expression of PPAR-γ and PPAR-γ target genes (LPL, GLT1, and IRAP/Lnpep), and inflammatory markers (TNF-α, IL-1β, IL-6, and iNOS), at 15 min, 3 h, 6 h, 12 h, and 24 h post-trauma; (2) contusion volume, neurological function, and gene expression after 24 h in mice treated with pioglitazone (0.5 and 1 mg/kg) or rosiglitazone (5 and 10 mg/kg IP at 30 min post-trauma); and (3) the role of PPAR-γ to mediate protection was determined in animals treated with pioglitazone, the PPAR-γ inhibitor T0070907, and a combination of both. Inflammatory marker genes, but not PPAR-γ gene expression, was upregulated after trauma. Pioglitazone reduced the histological damage and inflammation in a dose-dependent fashion. In contrast, rosiglitazone failed to suppress inflammation and histological damage. PPAR-γ and PPAR-γ target gene expression was not induced by pioglitazone and rosiglitazone. In line with these results, pioglitazone-mediated protection was not reversed by T0070907. The results indicate that the neuroprotective effects of pioglitazone are not solely related to PPAR-γ-dependent mechanisms.