Neovessels within human coronary atherosclerotic lesions are frequently observed, but their pathophysiological significance is still subject to debate. Also, the origin of these vessels and their pathways in the arterial wall are not well-known. In this study, we describe the transmural pathway and the frequency of neovessels both in vivo and in autopsy cases. Atherosclerotic coronary arteries were obtained during autopsy in 10 subjects without previous cardiovascular symptoms. In 25 patients undergoing percutaneous intervention for either stable or unstable angina, plaque fragments were retrieved by directional coronary atherectomy. In the autopsy study, at least one coronary artery in each case showed some degree of neointimal proliferation, characterized by smooth muscle cells in a dense extracellular matrix. A neovascularization process was seen in 17.5% of the 40 samples analyzed. In 2 cases, the transmural pathway of the neovessels could be tracked: serial sections revealed the emergence of an arteriole from the adventitia of the coronary artery, its transmedial course as a capillary, and its opening into the coronary arterial lumen. In symptomatic patients who underwent atherectomy, neovessels were found in 1 of 9 patients with stable angina (11%) and in 8 of 16 patients with unstable angina (50%, P < 0.05). Mostly, the neovessels appeared as capillaries cut in their short axis. In 2 cases, however, the capillary was seen in its longitudinal axis, and its pathway could be traced through the atherosclerotic lesion to its opening in the coronary lumen, as in the autopsy study. Therefore, neovessels frequently develop in the atherothrombotic plaque, both in asymptomatic and anginal patients. In the latter group, the proliferation of neovessels is more frequent in acute coronary syndromes. These findings have several implications, in particular for percutaneous coronary angioplasty and related procedures, such as local drug delivery.