High-resolution, two-dimensional transthoracic echocardiography (HR-2DTTE) can detect the difference in the left anterior descending coronary artery (LAD) wall thickness between patients with coronary artery disease and patients with normal coronary arteries. However, HR-2DTTE measurements of the LAD wall thickness are larger than measurements obtained by intravascular ultrasound and histology. This difference may be due to the inclusion of adventitia by HR-2DTTE. We evaluated the contribution of adventitia to the wall thickness of the normal and atherosclerotic LAD by comparing HR-2DTTE with high-frequency epicardial echocardiography. The LAD wall thickness was significantly greater in patients with coronary artery disease by both HR-2DTTE and high-frequency epicardial echocardiography. Both an increase in the intima plus media thickness and an increase in the thickness of adventitia contributed to the increase in the LAD wall thickness in patients with coronary artery disease. Adventitia represents a significant portion of the LAD wall thickness imaged by HR-2DTTE and its thickness increases significantly with the development of atherosclerosis.