We have found that jejunal infusions of long-chain fatty acids, linoleic acid (LA) and oleic acid (OA), and gastric infusions of a fatty acid ethyl ester, ethyl oleate (EO), produce long-lasting suppression of total caloric intake. This effect is not seen in response to jejunal infusions of medium-chain fatty acids or medium- or long-chain triglycerides. Multiunit recordings have shown that intestinal infusions of LA or OA strongly activate celiac vagal afferents. Truncal vagotomy (TVX) and selective celiac-branch vagotomy (CVX) are equally effective in attenuating, but not eliminating, suppression of food intake by LA and EO. These outcomes suggest that intraintestinal fatty acids reduce intake by activation of vagal mechanisms, critically involving afferent fibers within the celiac branches, as well as unidentified nonvagal mechanisms. The role of cholecystokinin (CCK) in mediating the activation of celiac vagal afferents is suggested by studies showing that (1) inhibition of food intake by CCK-8 administration is attenuated after CVX but robust after celiac-spared vagotomy (CSV), (2) multiunit activity of celiac vagal afferents is increased by CCK-8 administration, and (3) activation of celiac fibers by intestinal LA infusion is severely attenuated by the CCKA antagonist lorglumide. © 2004 Elsevier Inc. All rights reserved.