BACKGROUND: The carnitine O-palmitoyltransferase I (EC 220.127.116.11) inhibitor etomoxir inhibits fatty acid oxidation, and hepatic fatty acid oxidation has been suggested to be a metabolic satiety signal in subjects who consume high-fat diets. OBJECTIVE: We investigated substrate oxidation and satiety after repeated administrations of etomoxir or placebo in subjects who consumed a high-fat diet. DESIGN: In a randomized crossover design consisting of three 5-d treatments, we fed 10 healthy men [mean +/- SE age: 25.6 +/- 1.7 y; mean +/- SE body mass index (in kg/m(2)): 21.8 +/- 0.3] a high-fat diet twice and a low-fat diet once. The subjects consumed each diet at home for 3 consecutive days, after which they spent 36 h in energy balance in a respiration chamber. During the chamber stays with the high-fat treatments, etomoxir or placebo was administered in 5 doses (600 mg etomoxir in total). Blood samples were obtained on the mornings of days 4 and 5 of each treatment, and appetite profiles were assessed. RESULTS: Mean (+/-SE) 24-h respiratory quotients were significantly (P < 0.05) higher with repeated administrations of etomoxir (0.833 +/- 0.004) than with repeated administrations of placebo (0.814 +/- 0.006), and mean (+/-SE) 24-h whole-body fat oxidation tended to be less (13.7%, P = 0.06) with administration of etomoxir (136.0 +/- 5.2 g/d) than with administration of placebo (157.5 +/- 5.6 g/d). With the etomoxir treatment, fat balance was positive (P < 0.0001) and carbohydrate balance was negative (P < 0.001), whereas with the placebo treatment, neither of the balances was significantly different from zero. Hunger and satiety ratings were not affected under these conditions. CONCLUSIONS: Etomoxir decreased whole-body fat oxidation, as indicated by the respiratory quotients in the healthy subjects. With the current protocol, however, hunger and satiety ratings were not affected.