Neovascularization is well known to occur in human atherosclerotic plaques; however, its pathophysiological roles, mechanisms, and stimuli in atherogenesis still remain unclear. In this study, 525 tissue blocks of coronary artery tissue obtained at autopsy from 48 patients ranging in age from 20 to 93 years old (mean+/-SD, 71+/-15 years) were immunohistochemically examined for vascular endothelial growth factor (VEGF) expression in the atherosclerotic intimas. The atherosclerotic lesions were histopathologically classified into types I through VI, as proposed by the American Heart Association Committee, and the numbers of intimal blood vessels and VEGF-positive cells were then morphometrically counted in sections that were immunohistochemically examined with anti-CD34 and human VEGF antibodies, respectively. The more the atherosclerotic lesion type advanced, the more often the lesion contained intimal blood vessels, which were expressed as percentages of the intimal section with intimal microvessels, viz, diffuse intimal thickening (DIT): 0% (0/111); type I, 31% (32/104); II, 42% (10/24); III, 66% (77/117); IV, 72% (48/67); V, 79% (70/89); and VI, 100% (13/13), P<0.0001. The number of VEGF-positive cells per intimal section was also positively correlated with the number of intimal blood vessels (P<0. 0001). The VEGF-positive cells were scattered in the fibrous caps as well as the shoulders and deeper areas of the plaques, and the double-immunostaining method revealed that the VEGF-positive cells were largely spindle-shaped, smooth muscle cells with some macrophage-derived foam cells. These findings thus suggest the possibility that the VEGF expressed by the smooth muscle cells and foamy macrophages in the atherosclerotic intimas can act as a local and endogenous regulator of endothelial cell functions, including intimal neovascularization, in atherosclerotic lesions of human coronary arteries.