Left anterior descending coronary artery (LAD) wall thickness and external diameter are significantly increased in patients with coronary artery disease compared with normal subjects. High-resolution, 2-dimensional transthoracic echocardiography (HR-2DTTE) can be used to measure LAD wall thickness and is sensitive enough to detect these differences. However, HR-2DTTE measurements of the LAD wall thickness are larger than measurements obtained by intravascular ultrasound and histology. We hypothesize that this difference is due to inclusion of the third vascular layer, which may represent adventitia, by HR-2DTTE, and that this layer must be increasing in thickness with the development of atherosclerosis. We evaluated the contribution of this third layer to the wall thickness of the normal and atherosclerotic LAD imaged by HR-2DTTE using high-frequency epicardial echocardiography (HFEE). Thirteen patients with coronary atherosclerosis and 5 patients with normal coronary arteries underwent preoperative HR-2DTTE and intraoperative HFEE. HR-2DTTE and HFEE measurements of the wall thickness correlated well. The wall thickness was significantly greater in patients with coronary atherosclerosis than in patients with normal coronary arteries by both HR-2DTTE and HFEE. With HFEE, the average intima plus media thickness and the average thickness of adventitia were greater in patients with coronary atherosclerosis than in patients with normal coronary arteries. A third vascular layer, which likely includes adventitia, represents a significant portion of the LAD wall thickness imaged by HR-2DTTE and HFEE, and its thickness increases significantly with the development of atherosclerosis.