Leptin signaling may promote atherothrombosis and lead to cardiovascular disease. However, whether leptin is associated with human atherosclerosis, distinct from thrombosis, is unknown. We determined the association of plasma leptin levels with coronary artery calcification (CAC), a measure of coronary atherosclerosis, in a cross-sectional study of type 2 diabetes. Leptin levels were associated with CAC after adjusting for established risk factors [odds ratio (95% confidence interval) for 5 ng/ml leptin increase: 1.31 (1.10-1.55); P = 0.002]. Leptin remained associated with CAC after further controlling for body mass index (BMI) [1.29 (1.07-1.55); P = 0.008], waist circumference [1.30 (1.09-1.57); P = 0.003], C-reactive protein (CRP) levels [1.28 (1.07-1.55); P = 0.008], and subclinical vascular disease [1.30 (1.08-1.57); P = 0.006]. Addition of BMI (P = 0.97), waist (P = 0.55), or CRP (P = 0.39) to a model with leptin failed to improve the model's explanatory power, whereas addition of leptin to a model with BMI (P = 0.029), waist (P = 0.006), or CRP (P = 0.005) improved the model significantly. Plasma leptin levels were associated with CAC in type 2 diabetes after controlling adiposity and CRP. Whether leptin signaling promotes atherosclerosis directly or represents a therapeutic target for the prevention of atherosclerotic cardiovascular disease remains to be explored.