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Background: Mac-2 binding protein (M2BP) is a proinflammatory protein associated with atherosclerosis and prognosis in patients with coronary artery diseases. We aimed to investigate the expression of M2BP in human carotid plaques and its relation to clinical symptoms and components within plaques. Methods: Patients (n = 51) undergoing carotid endarterectomy were consecutively recruited in our study. M2BP expression was evaluated at three different levels: plasma, mRNA expression and immunohistochemical staining. Results: We found that (1) M2BP was mainly expressed by CD68+ macrophages but rarely expressed by smooth muscle cells (SMC) within plaques; (2) Expression of M2BP was elevated in advanced plaques with necrotic cores(Type II)and ruptured plaques(Type III)than fibrous intact plaques (Type I); (3) Increased expression of M2BP was observed in vulnerable sites (shoulder regions, areas surrounding the necrotic core and ruptured fibrous cap) of carotid plaques; (4) Symptomatic patients showed higher expression of M2BP than asymptomatic patients, especially those with severe symptoms and short duration since latest symptom onset; (5) Echolucent and heterogeneous plaques were observed to own elevated M2BP expression than echogenic plaques; (6) M2BP expression level was positively correlated with macrophage content and apoptotic level within plaques but negatively correlated with SMC and collagen content of plaques. Conclusions: M2BP is highly expressed in advanced plaques and vulnerable regions and significantly correlated with clinical ischemic manifestations. Therefore, M2BP may serve as an important biomarker of plaque destabilization.