Background: Despite the popularity of low-glycemic index (GI) and high-protein diets, to our knowledge no randomized, controlled trials have systematically compared their relative effects on weight loss and cardiovascular risk. Methods:Atotal of 129 overweight or obese young adults (body mass index, ≥25 [calculated as weight in kilograms divided by the square of height in meters]) were assigned to 1 of 4 reduced-fat, high-fiber diets for 12 weeks. Diets 1 and 2 were high carbohydrate (55% of total energy intake), with high and low GIs, respectively; diets 3 and 4 were high protein (25% of total energy intake), with high and low GIs, respectively. The glycemic load was highest in diet 1 and lowest in diet 4. Changes in weight, body composition, and blood chemistry profile were studied. Results: While all groups lost a similar mean±SE percentage of weight (diet 1, -4.2%±0.6%; diet 2, -5.5%±0.5%; diet 3, -6.2%±0.4%; and diet 4, -4.8%±0.7%; P=.09), the proportion of subjects in each group who lost 5% or more of body weight varied significantly by diet (diet 1, 31%; diet 2, 56%; diet 3, 66%; and diet 4, 33%; P=.01). Women on diets 2 and 3 lost approximately 80% more fat mass (-4.5±0.5 [mean±SE] kg and -4.6±0.5 kg) than those on diet 1 (-2.5±0.5 kg; P=.007). Mean±SE low-density-lipoprotein cholesterol levels declined significantly in the diet 2 group (-6.6±3.9 mg/dL [-0.17±0.10 mmol/L]) but increased in the diet 3 group (+10.0 ± 3.9 mg/dL [+0.26±0.10 mmol/L]; P=.02). Goals for energy distribution were not achieved exactly: both carbohydrate groups ate less fat, and the diet 2 group ate more fiber. Conclusion: Both high-protein and low-GI regimens increase body fat loss, but cardiovascular risk reduction is optimized by a high-carbohydrate, low-GI diet.