Leptin has been linked to adiposity, insulin resistance, and coronary artery disease (CAD). We examined whether the leptin concentrations are associated with the risk of CAD and metabolic syndrome (MS). The plasma leptin concentrations were measured in 556 diabetic patients (341 men and 215 women). The odds ratio (OR) of CAD and MS were increased on moving from the lowest quartile (Q1) of leptin concentration to the highest quartile (Q4) and remained significant after adjusting for age, sex, BMI, concentrations of total cholesterol, triglyceride, or high-sensitivity C-reactive protein (hsCRP), and treatment modalities for hyperglycemia. The frequency of CAD was highest in the insulin resistant group (Q4 of homeostasis model assessment-insulin resistance index [HOMA-IR]) at Q4 of leptin concentration (34.5%), compared with that of Q4 of leptin (26.4%) or HOMA-IR (21.9%). In multivariate analysis, plasma leptin concentration was identified as the most significantly independent predictor for CAD (OR 10.24, 95% CI 3.01 to 45.05). Other variables with associated with CAD were age, sex, hypertension, low-HDL cholesterolemia, and hsCRP. In conclusion, hyperleptinemia might be an independent risk factor for CAD and MS in diabetic subjects. And the simultaneous measurement of insulin resistance and leptin concentration might be helpful for screening subjects with a high-risk of CAD.