Background: It is unclear whether energy-containing drinks, especially those sweetened with high-fructose corn syrup (HFCS), promote positive energy balance and thereby play a role in the development of obesity. Objective: The objective was to examine the satiating effects of HFCS and sucrose in comparison with milk and a diet drink. Design: The effects of 4800-mL drinks containing no energy or 1.5 MJ from sucrose, HFCS, or milk on satiety were assessed, first in 15 men and 15 women with a mean (±SD) body mass index (BMI; in kg/m 2) of 22.1 ± 1.9 according to visual analogue scales (VAS) and blood variables and second in 20 men and 20 women (BMI: 22.4 ± 2.1) according to ingestion of a standardized ad libitum meal (granola cereal + yogurt, 10.1 kJ/g). Results: Fifty minutes after consumption of the 1.5-MJ preload drinks containing sucrose, HFCS, or milk, 170%-mm VAS changes in satiety were observed. Glucagon-like peptide 1 (GLP-1) (P < 0.001) and ghrelin (P < 0.05) concentrations changed accordingly. Compensatory energy intake did not differ significantly between the 3 preloads and ranged from 30% to 45%. Energy intake compensations were related to satiety (r = 0.35, P < 0.05). No differences were observed between the effects of the sucrose- and HFCS-containing drinks on changes in VAS and on insulin, glucose, GLP-1, and ghrelin concentrations. Changes in appetite VAS ratings were a function of changes in GLP-1, ghrelin, insulin, and glucose concentrations. Conclusion: Energy balance consequences of HFCS-sweetened soft drinks are not different from those of other isoenergetic drinks, eg, a sucrose-drink or milk.