Background: The prevention and treatment of obesity is a public health challenge. Objective: We investigated the effects of dietary composition, insulin sensitivity (SI), and energy balance on predicted changes in body composition. Design: In a randomized crossover design study, 39 normal-weight (n = 23), overweight (n = 8), and obese (n = 8) men and women (aged 25-36 y) each followed a 15-d isocaloric high-fat (HF; 50% fat) and high-carbohydrate [HC; 55% carbohydrate (CHO)] diet with a 4-6-wk washout period during the first year. During each treatment, energy balance was measured while the subjects were inactive by using indirect calorimetry on day 15, and S I was measured by using a euglycemic clamp study (40 mU · m-2· min-1) on day 16. Weight and body composition were then measured annually for 4 y. The outcomes for fat mass, percentage body fat, and weight were measured by using a linear 2-stage mixed model. Results: CHO balance (day 15) and SI (day 16) on the HC diet were highly and significantly correlated (r = 0.55, P < 0.001). On the HC diet, the subjects who had a higher positive CHO balance (day 15) gained less fat mass (P < 0.001), percentage body fat (P = 0.006), and weight (P = 0.024) over time. When adjusted for SI, CHO balance remained a significant predictor of changes in fat mass (P = 0.021) and percentage body fat (P = 0.025). Conclusions: On a HC diet, the subjects who had a higher positive CHObalance on day 15 while they were inactive gained less fat mass during 4 y, a predictive effect independent of SI. As suggested in rodents, the capacity to expand the glycogen pool might reduce energy intake and protect against fat and weight gain. © 2006 American Society for Nutrition.