Normal cellular prion protein (PrP(C)) has multiple functions but its role in the development of atherosclerosis has not been studied. Our pilot microarray data showed increased expression of PrP(C) in tissue samples of complicated carotid lesions. Therefore in this study, we aimed to investigate its localisation within atherosclerotic arteries and its concentration in patient plasma. PrP(C) expression was examined using an enzyme immunometric assay (EIA) in plasma from patients undergoing endarterectomy. Carotid specimens and control vascular transplants were studied for PrP(C) and CD105 (endoglin, a marker of active vessels) expression by immunohistochemistry and real-time PCR. Patients with carotid disease had higher levels of plasma PrP(C) than the control group [4.35 ng/ml (n = 22; 3.1-5.3) vs. 1.95 ng/ml (n = 21; 1.1-2.5), P < 0.001]. Furthermore, CD105-positive plaques had higher PrP(C) expression which colocalized with CD105 in neovessels. There was a significant correlation between mRNA expression of PrP(C) and CD105 in tested plaques (P < 0.001; r = 0.7) supporting our immunohistochemical findings. We conclude that PrP(C) is expressed in carotid specimens and may be associated with neovessel growth or survival in these plaques. Our results suggest a role for PrP(C) in modulating neovessel formation in complicated plaques.