Technical Abstract: Context: Compared with glucose-sweetened beverages, consumption of fructose-sweetened beverages with meals elevates postprandial plasma triglycerides and lowers 24-h insulin and leptin profiles in normal weight women. The effects of fructose, compared with glucose, ingestion on metabolic profiles in obese subjects has not been studied. Objective: Compare the effects of fructose and glucose-sweetened beverages consumed with meals on hormones and metabolic substrates in obese subjects. Design and Setting: Within subject design conducted in the Clinical and Translational Research Center. Participants: 17 obese men (n=9) and women (n=8), BMI >30 kg/m2. Interventions: Subjects were studied under two conditions involving ingestion of mixed nutrient meals with either glucose-sweetened beverages or fructose-sweetened beverages. The beverages provided 30% of total kilocalories. Blood samples were collected over 24-h. Main Outcome Measures: Area under the curve (24 h AUC) for glucose, lactate, insulin, leptin, ghrelin, uric acid, triglycerides (TGs), and free fatty acids. Results: Compared with glucose-sweetened beverages, fructose consumption was associated with lower AUCs for insulin (1052.6 ± 135.1 vs 549.2 ± 79.7 µU/ml . 23 h, p<0.001), leptin (151.9 ± 22.7 vs. 107.0 ± 15.0 ng/ml . 24 h, p<0.03) and increased AUC for TG (242.3 ± 96.8 vs 704.3 ± 124.4 mg/dl . 24 h, p< 0.0001). Insulin resistant subjects exhibited larger 24 h TG profiles (p<0.03). Conclusions: In obese subjects, consumption of fructose-sweetened beverages with meals was associated with less insulin secretion, blunted diurnal leptin profiles and increased postprandial TG concentrations compared with glucose consumption. Increases of TG were augmented in obese subjects with insulin resistance, suggesting that fructose consumption may exacerbate an already adverse metabolic profile present in many obese subjects.