Neovascularization in the walls of coronary arteries is associated with the presence of atherosclerotic plaque. The mechanisms responsible for the formation of these intraplaque microvessels are not understood. The purpose of this study is to examine the prevalence of endothelial cell replication in plaque microvessels. Two hundred and one primary and restenotic coronary atherectomy specimens were analyzed for the presence of microvessels and proliferation as reflected by positive immunolabeling for Ulex agglutinin and the proliferating cell nuclear antigen, respectively. In primary but not restenotic specimens, proliferation of any cell type was associated with the detection of microvessels on the same slide. However, intraplaque microvessels were more commonly found in restenotic compared to primary specimens (P = 0.004). Twelve highly vascularized specimens with evidence of replication were subjected to detailed histomorphological and quantitative image analyses. At 200 x, the most vascular optical field of each slide was identified and consistently included plaque macrophages. Total slide endothelial cell replication indices for these specimens varied, but in some instances were remarkably elevated (eg, 43.5%). The role of intraplaque angiogenesis may be analogous to that of tumor or wound angiogenesis and be important in development and progression of coronary artery lesions and restenosis.