Context: Data supporting physical activity guidelines to prevent long-term weight gain are sparse, particularly during the period when the highest risk of weight gain occurs. Objective: To evaluate the relationship between habitual activity levels and changes in body mass index (BMI) and waist circumference over 20 years. Design, Setting, and Participants: The Coronary Artery Risk Development in Young Adults (CARDIA) study is a prospective longitudinal study with 20 years of follow-up, 1985-1986 to 2005-2006. Habitual activity was defined as maintaining high, moderate, and low activity levels based on sex-specific tertiles of activity scores at baseline. Participants comprised a population-based multicenter cohort (Chicago, Illinois; Birmingham, Alabama; Minneapolis, Minnesota; and Oakland, California) of 3554 men and women aged 18 to 30 years at baseline. Main Outcome Measures: Average annual changes in BMI and waist circumference. Results: Over 20 years, maintaining high levels of activity was associated with smaller gains in BMI and waist circumference compared with low activity levels after adjustment for race, baseline BMI, age, education, cigarette smoking status, alcohol use, and energy intake. Menmaintaining high activity gained 2.6 fewer kilograms per year (+0.15 BMI units; 95% confidence interval [CI], 0.11-0.18 vs +0.20 in the lower activity group; 95% CI, 0.17-0.23), and women maintaining higher activity gained 6.1 fewer kilograms per year (+0.17 BMI units; 95% CI, 0.12-0.21 vs +0.30 in the lower activity group; 95% CI, 0.25-0.34). Men maintaining high activity gained 3.1 fewer centimeters in waist circumference per year (+0.52 cm; 95% CI, 0.43-0.61 cm vs 0.67 cm in the lower activity group; 95% CI, 0.60-0.75 cm) and women maintaining higher activity gained 3.8 fewer centimeters per year (+0.49 cm; 95% CI, 0.39-0.58 cm vs 0.67 cm in the lower activity group; 95% CI, 0.60-0.75 cm). Conclusion: Maintaining high activity levels through young adulthood may lessen weight gain as young adults transition to middle age, particularly in women.