Peroxisome proliferator-activated receptor (PPAR)-β/Î′ is a transcription factor that belongs to the PPAR nuclear hormone receptor family. There is little information about the ligands of PPAR-β/Î′ and the effect of specific activation (eg, GW0742) of PPAR-β/Î′ in animal models of shock. Here we used PPAR-β/Î′ knockout (ko) mice to investigate the role of this transcription factor in a lipopolysaccharide-induced model of cardiac dysfunction and organ injury/inflammation. When challenged with lipopolysaccharide (9 mg/kg intraperitoneally) for 16 h, ko mice exhibited a significant reduction in cardiac function when compared with wild-type (wt) mice, as revealed by echocardiography. When compared with wt mice, ko mice exhibited significantly increased serum levels of creatinine (renal dysfunction) and alanine aminotransferase (hepatocellular injury). In C57/BL6 mice, administration of the highly selective PPAR-β/Î′ agonist GW0742 (0.03 mg/kg intravenously) 1 h after lipopolysaccharide challenge significantly attenuated the cardiac dysfunction caused by lipopolysaccharide-induced endotoxaemia, as revealed by echocardiography and the isolated-perfused Langendorff heart. Pre-treatment with a highly selective PPAR-β/Î′ antagonist GSK0660 (0.1 mg/kg intravenously) 30 minutes before lipopolysaccharide reduced the cardioprotective effect of GW0742. When compared with mice challenged with lipopolysaccharide alone, GW0742 significantly attenuated creatinine serum levels and lung myeloperoxidase activity (lung inflammation). Our results suggest potential physiological ligands of PPAR-β/Î′, which can afford a protective role in lipopolysaccharide-induced cardiac dysfunction and organ injury, as indicated by the loss of the receptor. Subsequently, activation of the receptor with a specific agonist, GW0742, inhibits the cardiac dysfunction and organ injury/inflammation caused by lipopolysaccharide-induced endotoxemia.