Citotoxin-associated gene-A (CagA)-positive Helicobacter pylori strains have been associated with occurrence and destabilization of coronary atherosclerotic plaques. However, data on the relationship between CagA-positive H. pylori infection and carotid artery instability are lacking. Thus, the role of CagA antigen in patients with symptomatic and asymptomatic carotid atherosclerotic plaques was investigated. A total of 64 patients with advanced carotid artery stenosis, including 33 patients with symptomatic and 31 patients with asymptomatic internal carotid artery stenosis, verified by duplex ultrasound, all undergoing carotid endarterectomy, were studied. The control group consisted of 65 subjects without a history or presence of vascular diseases. Serology for H. pylori and CagA antigen was assessed in all participants. Specimens of atherosclerotic plaques obtained from all patients during carotid endarterectomy were analyzed immunohistochemically using anti-CagA monoclonal antibodies. The ultrasonographic plaque characteristics were also estimated. CagA antibody titers were significantly higher in symptomatic patients (8.8; range, 5.8-32.7) compared to asymptomatic patients (4.7; range, 2.1-8.8; P = 0.005) and the control group (5.0; range 2.2-7.9; P < 0.001). There was significant difference in echolucency (≥ 25% soft material) between the symptomatic and asymptomatic groups (P = 0.034) by ultrasonographic evaluation. Positive immunoreactivity between monoclonal CagA antibodies and antigens within atherosclerotic specimens was significantly higher among symptomatic patients compared to asymptomatic patients (97.0 vs. 74.2%; P = 0.009). H. pylori may play a role in the pathogenesis of the atherosclerotic process due to autoimmune mechanisms and even contribute to destabilization of carotid atherosclerotic plaques.