Troglitazone is an oral antidiabetic drug that is a ligand for peroxisome proliferator activated receptor gamma (PPARgamma). Based on other studies that have implicated an immunosuppressive role for PPARgamma during inflammatory responses, we hypothesized that troglitazone treatment would improve survival in a murine model of endotoxemia and that the protective effect would be mediated by decreased expression of inflammatory mediators. C57Bl/6N x Sv/129 (wild-type [WT]) or PPARalpha null mice treated for 2 weeks with dietary troglitazone (0.1%) had significantly fewer deaths and a higher LD(50) value compared to control-fed mice when challenged with lipopolysaccharide (LPS). PPARalpha null mice were more sensitive to the lethal effects of LPS as evidenced by a 2-fold lower LD(50) (6.6 mg/kg) compared to WT mice (14.6 mg/kg). Troglitazone treatment had no significant effect on LPS-induced plasma TNF, glucose, or nitric oxide levels in WT or PPARalpha null mice at any of the time points examined. However, troglitazone treatment significantly reduced LPS-induced plasma IL-6 levels in both WT and PPARalpha null mice. The results of these studies suggest that troglitazone treatment protects mice against a lethal challenge of LPS, but whether or not this effect is mediated through decreased expression of inflammatory mediators remains unclear.