The aims of this study were to determine whether dipeptidyl peptidase IV (DPP-IV) inhibition would enhance plasma active incretin [glucose-dependent insulinotropic polypeptide (GIP), GLP-1] concentrations and modulate the glycemic, gut hormone, triglyceride, energy expenditure, and energy intake responses to intraduodenal fat infusion. In a double-blind, randomized, placebo-controlled crossover design, 16 healthy lean males received 50 mg vildagliptin (V), or matched placebo (P), before intraduodenal fat infusion (2 kcal/min, 120 min). Blood glucose, plasma insulin, glucagon, active GLP-1, and GIP and peptide YY (PYY)-(3-36) concentrations; resting energy expenditure; and energy intake at a subsequent buffet meal (time ϭ 120 -150 min) were quantified. Data are presented as areas under the curve (0 -120 min, means Ϯ SE). Vildagliptin decreased glycemia (P: 598 Ϯ 8 vs. V: 573 Ϯ 9 mmol·l Ϫ1 ·min Ϫ1 , P Ͻ 0.05) during intraduodenal lipid. This was associated with increased insulin (P: 15,964 Ϯ 1,193 vs. V: 18,243 Ϯ 1,257 pmol·l Ϫ1 ·min Ϫ1 , P Ͻ 0.05), reduced glucagon (P: 1,008 Ϯ 52 vs. V: 902 Ϯ 46 pmol·l Ϫ1 ·min Ϫ1 , P Ͻ 0.05), enhanced active GLP-1 (P: 294 Ϯ 40 vs. V: 694 Ϯ 78 pmol·l Ϫ1 ·min Ϫ1 ) and GIP (P: 2,748 Ϯ 77 vs. V: 4,256 Ϯ 157 pmol·l Ϫ1 ·min Ϫ1 ), and reduced PYY-(3-36) (P: 9,527 Ϯ 754 vs. V: 4,469 Ϯ 431 pM/min) concentrations compared with placebo (P Ͻ 0.05, for all). Vildagliptin increased resting energy expenditure (P: 1,821 Ϯ 54 vs. V: 1,896 Ϯ 65 kcal/day, P Ͻ 0.05) without effecting energy intake. Vildagliptin 1) modulates the effects of intraduodenal fat to enhance active GLP-1 and GIP, stimulate insulin, and suppress glucagon, thereby reducing glycemia and 2) increases energy expenditure. These observations suggest that the fat content of a meal, by enhancing GLP-1 and GIP secretion, may contribute to the response to DPP-IV inhibition.