Technical Abstract: Fructose consumption in the U.S. has increased over the past three decades. During this time, obesity, insulin resistance and the metabolic syndrome have increased in prevalence. While fructose- rich diets promote insulin resistance and hypertriglyceridemia in animals, there are insufficient data regarding the long-term effects of fructose consumption in humans. The objective of this study was to investigate and compare the metabolic/endocrine effects of long-term (10 week) consumption of fructose- or glucose-sweetened beverages in humans. Following a four-week weight-maintaining complex carbohydrate diet, subjects were fed an isocaloric diet, which included a fructose- or glucose-sweetened beverage with each meal, for ten weeks. Intervention diets provided 15% of energy from protein, 30% from fat, and 55% from carbohydrate (30% complex carbohydrate, 25% glucose or fructose). Eleven overweight to obese (BMI range 26-35 kg/m2) post-menopausal women were studied in a controlled metabolic setting. Main outcome measures included fasting and postprandial glucose, insulin, leptin, triglyceride, and apolipoprotein-B concentrations. Fructose consumption increased fasting glucose concentrations (4.6 ± 0.1 mmol/l at baseline vs. 4.9 ± 0.1 at 2 and 10 weeks, p<0.001) and decreased meal-associated glucose and insulin, and diurnal leptin excursions. At 10 weeks, subjects consuming fructose-, but not glucose-sweetened beverages, exhibited marked and prolonged postprandial hypertriglyceridemia and increased fasting apolipoprotein-B concentrations (p<0.05). The area under the curve for triglycerides was increased by 141% at 10 weeks (p<0.05). Consuming fructose- but not glucose-sweetened beverages increases circulating postprandial triglyceride and apolipoprotein-B concentrations in humans, suggesting that long-term consumption of diets high in fructose may increase the risk of cardiovascular disease.