Background: In light of the current obesity epidemic, treatment models are needed that can prevent weight gain or provide weight loss. We examined the long-term effects of a supervised program of moderate-intensity exercise on body weight and composition in previously sedentary, overweight and moderately obese men and women. We hypothesized that a 16-month program of verified exercise would prevent weight gain or provide weight loss in the exercise group compared with controls. Methods: This was a randomized controlled efficacy trial. Participants were recruited from 2 midwestern universities and their surrounding communities. One hundred thirty-one participants were randomized to exercise or control groups, and 74 completed the intervention and all laboratory testing. Exercise was supervised, and the level of energy expenditure of exercise was measured. Controls remained sedentary. All participants maintained ad libitum diets. Results: Exercise prevented weight gain in women and produced weight loss in men. Men in the exercise group had significant mean ± SD decreases in weight (5.2 ± 4.7 kg), body mass index (calculated as weight in kilograms divided by the square of height in meters) (1. 6 ± 1.4), and fat mass (4.9 ± 4.4 kg) compared with controls. Women in the exercise group maintained baseline weight, body mass index, and fat mass, and controls showed significant mean ± SD increases in body mass index (1.1 ± 2.0), weight (2.9 ± 5.5 kg), and fat mass (2.1 ± 4.8 kg) at 16 months. No significant changes occurred in fat-free mass in either men or women; however, both had significantly reduced visceral fat. Conclusions: Moderate-intensity exercise sustained for 16 months is effective for weight management in young adults.