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Previous studies have demonstrated that feelings of sleepiness increase after ingestion of a fat-rich meal. The aim of the study was to test the hypothesis that postprandial sleepiness is mediated by cholecystokinin (CCK) acting on CCK-A receptors. A double-blind crossover study was conducted. Twelve male volunteers ate a high-fat morning meal [54% energy fat, 41% energy carbohydrate (CHO)]. On one day they received an i.v. infusion of Loxiglumide, a CCK-A receptor antagonist (30 mg/kg/h for 10 min then 10 mg/kg/h for 3 h 10 min). On another day the protocol was repeated except a saline placebo infusion was given at similar rates as the Loxiglumide, starting 20 min before the meal. Subjects' mood and sleepiness were monitored throughout using questionnaires and performance tasks. The results indicate that ratings of vigour were significantly lower during the Loxiglumide infusion than during the saline infusion, [F(1,10) = 6.65; p = 0.027]. Subjects who were infused with Loxiglumide on their first test day felt significantly (p < 0.05) more fatigued, sleepy and tense and less vigorous, less efficient and had lower energetic arousal during the Loxiglumide infusion than during the saline infusion. In conclusion, the results suggest that the postprandial decline in feelings of alertness after a fat-rich meal is not mediated solely by CCK acting through CCK-A receptors.