Context: Weight loss elicits physiological adaptations relating to energy intake and expenditure that antagonize ongoing weight loss. Objective: To test whether dietary composition affects the physiological adaptations to weight loss, as assessed by resting energy expenditure. Design, Study, and Participants: A randomized parallel-design study of 39 over-weight or obese young adults aged 18 to 40 years who received an energy-restricted diet, either low-glycemic load or low-fat. Participants were studied in the General Clinical Research Centers of the Brigham and Women's Hospital and the Children's Hospital, Boston, Mass, before and after 10% weightless. The study was conducted from January 4, 2001, to May 6, 2003. Main Outcome Measures: Resting energy expenditure measured in the fasting state by indirect calorimetry, body composition by dual-energy x-ray absorptiometry, cardiovascular disease risk factors, and self-reported hunger. Results: Resting energy expenditure decreased less with the low-glycemic load diet than with the low-fat diet, expressed in absolute terms (mean [SE], 96  vs 176  kcal/d; P=.04) or as a proportion (5.9% [1.5%] vs 10.6% [1.7%]; P=.05). Participants receiving the low-glycemic load diet reported less hunger than those receiving the low-fat diet (P=.04). Insulin resistance (P=.01), serum triglycerides (P=.01), C-reactive protein (P=.03), and blood pressure (P=.07 for both systolic and diastolic) improved more with the low-glycemic load diet. Changes in body composition (fat and lean mass) in both groups were very similar (P=.85 and P=.45, respectively). Conclusions: Changes in dietary composition within prevailing norms can affect physiological adaptations that defend body weight. Reduction in glycemic load may aid in the prevention or treatment of obesity, cardiovascular disease, and diabetes mellitus.