Peroxisome proliferator-activated receptor delta (PPAR delta) is a ligand-activated transcription factor that has an important role in lipid metabolism. Activation of PPARd stimulates fatty acid oxidation in adipose tissue and skeletal muscle and improves dyslipidemia in mice and humans. PPARd is highly expressed in the intestinal tract but its physiological function in this organ is not known. Using mice with an intestinal epithelial cell-specific deletion of PPARd, we show that intestinal PPARd protects against diet-induced obesity, insulin resistance and dyslipidemia. Furthermore, absence of intestinal PPARd abolished the ability of PPARd agonist GW501516 to increase plasma levels of HDL-cholesterol. Together, our findings show that intestinal PPARd is important in maintaining metabolic homeostasis and suggest that intestinal-specific activation of PPARd could be a therapeutic approach for treatment of the metabolic syndrome and dyslipidemia, while avoiding systemic toxicity.