Technical Abstract: It has been proposed that the adverse metabolic effects of chronic consumption of sugar-sweetened beverages which contain both glucose and fructose are a consequence of increased circulating glucose and insulin excursions, i.e dietary glycemic index (GI). Objective: We determined if the greater adverse effects of fructose, compared with glucose consumption, were associated with glucose and insulin exposure. Research Design and Methods: Subjects were studied in a metabolic facility (CCRC) and consumed an energy-balanced diet containing 55% of energy as complex carbohydrate for 2 weeks (GI = 64). Subjects then consumed 25% of energy requirements as fructose- or glucose-sweetened beverages along with their usual ad libitum diets for 8 weeks at home, and then as part of an energy-balanced diet for 2 weeks at the CCRC (Fructose GI = 38, Glucose GI = 83). 24-h glucose and insulin profiles, and fasting plasma glycated albumin and fructosamine concentrations were measured before and after 2, 8, and 10 weeks of beverage consumption. Results: Consumption of fructose-sweetened beverages lowered glucose and insulin post-meal peaks and 23-h area under the curve, while consumption of glucose-sweetened beverages increased these parameters. Plasma glycated albumin concentrations were slightly (~3%) lower after 10 weeks fructose consumption, whereas fructosamine concentrations did not differ between groups. Conclusions: The adverse effects of fructose consumption are not mediated by increased glucose and insulin excursions. These results suggest that the specific effects of fructose, and not glucose and insulin excursions (GI), contribute to the adverse effects of consuming sugar-sweetened beverages on lipids and insulin sensitivity.