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Troglitazone is an oral antidiabetic drug that is a ligand for peroxisome proliferator activated receptor γ (PPARγ). Based on other studies that have implicated an immunosuppressive role for PPARγ 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 PPARα 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). PPARα 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 PPARα null mice at any of the time points examined. However, troglitazone treatment significantly reduced LPS-induced plasma IL-6 levels in both WT and PPARα 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.