Change and fluctuation in body mass index (BMI; weight (kg)/height (m)(2)) may be associated differently with coronary artery calcification (CAC) than with carotid artery intima-media thickness (IMT). The authors analyzed data on 2,243 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) Study, initially aged 18-30 years, who were examined every 2-5 years over a 20-year period (1985-2006). BMI at year 0 was associated positively and linearly with CAC at year 20; however, the association of BMI with year 20 CAC became progressively U-shaped in subsequent examinations (years 10, 15, and 20). To understand the deepening U shape, the authors modeled year 20 BMI and its history using 3 indices: year 0 BMI, linear slope of BMI during 20 years, and BMI fluctuation during 20 years. In models including these 3 terms, year 0 BMI was associated positively with CAC, as was BMI fluctuation. However, adjusted odds ratios across quintiles of BMI slope (vs. the lowest quintile) were 0.7, 0.4, 0.5, and 0.4 (P(trend) < 0.01), suggesting higher risk of CAC with weight loss, plateauing after moderate weight gain. In contrast, IMT was associated positively with BMI at all examinations and with 20-year BMI slope and was unassociated with BMI fluctuation. Surprisingly, CAC risk was higher with BMI loss and lower with BMI gain, whereas associations with IMT were as expected.