Background: Most atherosclerotic lesions are vascularized, so neovessels may also contribute to plaque progression and vulnerability, but their precise role of neovessels in atherosclerosis is still unknown. The aim of this study was to analyze the possible relationships among neovascularization, relevant angiogenic factors, and plaque vulnerability in patients with advanced carotid artery stenosis. Methods and Results: The study group comprised 56 patients (stable: n=28, unstable: n=28) with advanced carotid artery stenosis (>70%). Immunohistochemistry was performed for smooth muscle, endothelial, and inflammatory cells, macrophages, vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2), platelet-derived growth factor (PDGF), and angiopoietin-1,-2 (Ang-1,-2). Furthermore, the concentrations of angiogenic factors were measured in serum. Quantitative expression analysis was performed by SYBR-Green-based real-time polymerase chain reaction. Compared with stable carotid lesions, unstable carotid lesions showed 1.8-fold increase in neovascularization (P=0.013), which significantly correlated with accumulation of inflammatory cells (factor 1.9, P<0.001). In unstable lesions, compared with stable lesions, VEGF was 1.7-fold increased (P=0.032) and Ang-1 was 1.9-fold reduced (P=0.029). Furthermore, VEGF was higher in the blood of patients with unstable plaques than in stable plaques (0.32±0.22 vs. 0.22±0.16ng/ml; P=0.002). Significant correlations were observed between plaque vulnerability, VEGF, neovascularization and inflammatory cells. Conclusions: Our results show a close association between neovascularization, expression of angiogenic factors, inflammation, and plaque vulnerability in patients with advanced carotid stenosis. (Circ J 2012; 76: 1274-1282)