Previous studies have shown effects of high-protein diets, especially whey protein, on energy expenditure and satiety, yet a possible distinction between the effects of whey or alpha-lactalbumin has not been made. The present study assessed the effects of the addition of total whey protein (whey) or caseinomacropeptide-depleted alpha-lactalbumin-enriched whey protein (alpha-lac) to a breakfast yoghurt drink on energy expenditure and appetite suppression in human subjects. A total of eighteen females and seventeen males (aged 20.9 (sd 1.9) years; BMI 23.0 (sd 2.1) kg/m2) participated in an experiment with a randomised, three-arm, cross-over design where diet-induced energy expenditure, respiratory quotient and satiety were measured. Breakfasts were isoenergetic and subject-specific: a normal-protein (NP) breakfast consisting of whole milk (15, 47 and 38 % energy from protein, carbohydrate and fat, respectively), a high-protein (HP) breakfast with additional whey or a HP breakfast containing alpha-lac (41, 47 and 12 % energy from protein, carbohydrate and fat, respectively). Resting energy expenditure did not differ between the three conditions. HP breakfasts (area under the curve: whey, 217.1 (se 10.0) kJ x 4 h; alpha-lac, 234.3 (se 11.6) kJ x 4 h; P < 0.05) increased diet-induced thermogenesis more compared with a NP yoghurt at breakfast (179.7 (se 10.9) kJ x 4 h; P < 0.05). Hunger and desire to eat were significantly more suppressed after alpha-lac (hunger, - 6627 (se 823); desire to eat, - 6750 (se 805) mm visual analogue scale (VAS) x 4 h; P < 0.05) than after the whey HP breakfast (hunger, - 5448 (se 913); desire to eat, - 5070 (se 873) mm VAS x 4 h; P < 0.05). After the HP breakfasts, a positive protein balance occurred (alpha-lac, 0.35 (sd 0.18) MJ/4 h; whey, 0.37 (sd 0.20) MJ/4 h; P < 0.001); after the NP breakfast a positive fat balance occurred (1.03 (sd 0.29) MJ/4 h; P < 0.001). In conclusion, consumption of a breakfast yoghurt drink with added whey or alpha-lac increased energy expenditure, protein balance and decreased fat balance compared with a NP breakfast. The alpha-lac-enriched yoghurt drink suppressed hunger and the desire to eat more than the whey-enriched yoghurt drink.