CONTEXT: Leptin is associated with adiposity and insulin resistance and may play a direct role in vascular calcification. It is unclear, however, whether leptin is an independent predictor of atherosclerotic burden. OBJECTIVE: The aim of this study was to examine the association between plasma leptin and coronary artery calcification (CAC) in an ethnically diverse cohort of older adult men and women free of clinical cardiovascular disease. DESIGN: This was a cross-sectional study with data collection between January 2002 and February 2004 as part of the ADVANCE Study. SETTING: The study was conducted at an integrated health care delivery system in Northern California. PARTICIPANTS: Participants included 949 men and women aged 60-69 yr old. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURE: The main outcome measure was CAC by multidetector row computed tomography. RESULTS: In ordinal logistic regression, plasma leptin levels were positively associated with extent of CAC independently of age, race/ethnicity, and smoking status in women (odds ratio of higher CAC for the sex-specific upper tertile vs. lower tertile = 1.81; 95% confidence interval, 1.10-3.00) but not in men (odds ratio = 1.29; 95% confidence interval = 0.89-1.86). However, this association was explained by metabolic risk factors and adiposity measures. CONCLUSIONS: Our findings support a role of leptin on vascular calcification in women but, in our sample of older adults, the association between leptin and CAC was not independent of other cardiac risk factors.