The process begins with the seepage of cholesterol from the blood into the inner layers of the arterial wall, with the formation of what are called fatty streaks. Another factor is injury to the endothelium, which is a thin layer of cells lining the inner wall of the artery. This injury may be of chemical origin, (for example nicotine), or it may be mechanical (the wear and tear of blood flow, particularly at branch points in the vessels where the flow becomes turbulent).

When as a result of these injuries, the endothelium gets torn, platelets and white cells from the blood stick onto the bare area. Platelets are the smallest of the circulating blood cells, whose main function is damage control by sticking to any injured area of the arterial wall and initiating the clotting process. If the injuries continue, some of these cells may burrow into the wall of the artery and start to form a local swelling, which begins to encroach on the lumen of the artery, that is the space through which the blood flows. More cholesterol accumulates in these plaques, and can be seen as crystals when examined under the microscope. The protruding plaque causes further turbulence of the blood flowing past it, and the stretching of the endothelium covering the plaque makes it liable to further damage.