Rupture of atherosclerotic plaques and the resulting thrombosis are vital causes of clinical ischemic events. Recent studies have shown that ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4) is a pathogenic factor of plaque vulnerability in mice. However, the relationship between ADAMTS4 and carotid atherosclerotic vulnerable plaques in humans remains unclear.Forty-eight carotid atherosclerotic plaque specimens were obtained from 48 carotid artery stenosis inpatients undergoing carotid endarterectomy. We performed hematoxylin and eosin and Movat pentachrome staining for histologic characteristics; immunohistochemical staining for ADAMTS4, versican, and macrophages; and serologic tests for ADAMTS4. Patients were divided into stable and vulnerable groups on the basis of histologic characterization according to the classification criteria of the American Heart Association. Comparison between the groups was carried out using SPSS 17.0 (SPSS Inc, Chicago, Ill).Expression of ADAMTS4 in the plaque and its serum concentration were significantly higher in the vulnerable group compared with the stable one (P = .004 and P = .021, respectively), whereas the expression of versican was lower in the vulnerable group than in the stable group (P = .015). Univariate analysis revealed that the incidence of symptomatic cerebral ischemic events and ADAMTS4 serum levels were statistically higher in the vulnerable group compared with the stable group (P = .021 and P = .029, respectively). Multivariate analysis showed that ADAMTS4 was an independent risk factor (odds ratio, 1.14; P = .038).Our study revealed that ADAMTS4 expression was upregulated during carotid atherosclerotic plaque development. Serum levels of ADAMTS4 were associated with increased plaque vulnerability in both symptomatic and asymptomatic patients with carotid artery stenosis. ADAMTS4 may be a potential biomarker for plaque vulnerability.