Oral sensory signals drive dietary fat intake, but the neural mechanisms underlying this process are largely unknown. The endocannabinoid system has gained recent attention for its central and peripheral roles in regulating food intake, energy balance, and reward. Here, we used a sham-feeding paradigm, which isolates orosensory from postingestive influences of foods, to examine whether endocannabinoid signaling participates in the positive feedback control of fat intake. Sham feeding a lipid-based meal stimulated endocannabinoid mobilization in the rat proximal small intestine by altering enzymatic activities that control endocannabinoid metabolism. This effect was abolished by surgical transection of the vagus nerve and was not observed in other peripheral organs or in brain regions that control feeding. Sham feeding of a nutritionally complete liquid meal produced a similar response to that of fat, whereas protein or carbohydrate alone had no such effect. Local infusion of the CB1-cannabinoid receptor antagonist, rimonabant, into the duodenummarkedly reduced fat sham feeding. Similarly to rimonabant, systemic administration of the peripherally restricted CB1-receptor antagonist, URB 447, attenuated sham feeding of lipid. Collectively, the results suggest that the endocannabinoid system in the gut exerts a powerful regulatory control over fat intake and might be a target for antiobesity drugs.