Context: The role of endogenous androgens and SHBG in the development of cardiovascular disease in young adult women is unclear. Objective: Our objective was to study the prospective association of serum androgens and SHBG with subclinical coronary and carotid disease among young to middle-aged women. Design and Setting: This was an ancillary study to the Coronary Artery Risk Development in Young Adults (CARDIA) study, a population-based multicenter cohort study with 20 yr of follow-up. Participants: Participants included 1629 women with measurements of serum testosterone and SHBG from yr 2, 10, or 16 and subclinical disease assessment at yr 20 (ages 37-52 yr). Main Outcome Measures: Coronary artery calcified plaques (CAC) and carotid artery intima-media thickness (IMT) were assessed at yr 20. The IMT measure incorporated the common carotid arteries, bifurcations, and internal carotid arteries. Results: SHBG (mean of yr 2, 10, and 16) was inversely associated with the presence of CAC (multivariable adjusted odds ratio for women with SHBG levels above the median = 0.59; 95% confidence interval = 0.40-0.87; P = 0.008). SHBG was also inversely associated with the highest quartile of carotid-IMT (odds ratio for women with SHBG levels in the highest quartile = 0.56; 95% confidence interval = 0.37-0.84; P for linear trend across quartiles = 0.005). No associations were observed for total or free testosterone with either CAC or IMT. Conclusion: SHBG levels were inversely associated with subclinical cardiovascular disease in young to middle-aged women. The extent to which low SHBG is a risk marker or has its own independent effects on atherosclerosis is yet to be determined. Copyright © 2010 by The Endocrine Society.