High-protein (HP) foods are more satiating and have a higher thermogenic effect than normal protein foods over the short-term as well as the long-term. We hypothesized that acute effects of higher protein intake on satiety may be related to acute metabolic and hormonal responses. The study was a single-blind, randomized, crossover design. Subjects underwent 2 indirect calorimetry tests for measurement of energy expenditure (EE) and substrate oxidation. After a standard subject-specific breakfast, subjects received 1 of 2 randomly assigned treatments: an appropriate protein (AP) lunch (10% energy (E) protein, 60%E carbohydrate, 30%E fat), or a HP lunch (25%E protein, 45%E carbohydrate, 30%E fat). The increase in postlunch EE tended to be greater after the HP lunch (0.85 ± 0.32 kJ/min) than after the AP lunch (0.73 ± 0.22 kJ/min) (P = 0.07). The respiratory quotient did not differ between the HP (0.84 ± 0.04) and the AP (0.86 ± 0.04) treatments. Satiety visual analogue scales (VAS) scores were significantly higher 30 and 120 min after the HP lunch than after the AP lunch. The area under the curve of the VAS score for satiety was higher after the HP lunch (263 ± 61 mm/h) than after the AP lunch (AP 236 ± 76 mm/h) (P < 0.02). Effects of the meals on satiety and diet-induced thermogenesis did not occur simultaneously with changes in plasma ghrelin, glucagon-like peptide 1, and peptide tyrosine-tyrosine concentrations. A single HP lunch, therefore, does not exert its acute effect on satiety through increased concentrations of satiety-related hormones. Other factors, which may explain the HP effect on satiety, may be metabolites or amino acids.