Obesity and high-fructose corn syrup (HFCS)-sweetened beverages are associated with an increased risk of chronic disease, but it is not clear whether obese (Ob) individuals are more susceptible to the detrimental effects of HFCS-sweetened beverages. The purpose of this study was to examine the endocrine and metabolic effects of consuming HFCS-sweetened beverages, and whether weight classification (normal weight (NW) vs. Ob) influences these effects. Ten NW and 10 Ob men and women who habitually consumed ≤355 mL per day of sugar-sweetened beverages were included in this study. Initially, the participants underwent a 4-h mixed-meal test after a 12-h overnight fast to assess insulin sensitivity, pancreatic and gut endocrine responses, insulin secretion and clearance, and glucose, triacylglycerol, and cholesterol responses. Next, the participants consumed their normal diet ad libitum, with 1065 mL per day (117 g·day(-1)) of HFCS-sweetened beverages added for 2 weeks. After the intervention, the participants repeated the mixed-meal test. HFCS-sweetened beverages did not significantly alter body weight, insulin sensitivity, insulin secretion or clearance, or endocrine, glucose, lipid, or cholesterol responses in either NW or Ob individuals. Regardless of previous diet, Ob individuals, compared with NW individuals, had ∼28% lower physical activity levels, 6%-9% lower insulin sensitivity, 12%-16% lower fasting high-density-lipoprotein cholesterol concentrations, 84%-144% greater postprandial triacylglycerol concentrations, and 46%-79% greater postprandial insulin concentrations. Greater insulin responses were associated with reduced insulin clearance, and there were no differences in insulin secretion. These findings suggest that weight classification does not influence the short-term endocrine and metabolic effects of HFCS-sweetened beverages.