Background: To evaluate the association of plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels with the progression of carotid atherosclerosis and identify additional PCSK9-lipoprotein-atherosclerosis pathway beyond low-density lipoprotein cholesterol (LDL-C). Methods: Among 643 participants (aged from 45 to 74 years) free of cardiovascular disease at baseline, carotid ultrasound examinations were performed in 2002 (baseline) and 2012 (follow-up). None of the participants were taking lipid-lowering drugs or had detectable carotid plaques at baseline. Carotid plaque formation and total plaque area (TPA) were used to reflect 10-year progression of atherosclerosis. Results: Baseline plasma PCSK9 levels have a wide variation, ranged from 64.60-532.20 ng/mL (median: 192.57 ng/mL). PCSK9 levels were significantly associated with new plaque formation after adjusting for LDL-C levels and other risk factors (relative risk for per quartile increase = 1.09, 95% confidence interval: 1.03-1.15). PCSK9 levels were also linearly associated with TPA after multivariate adjustment including LDL-C (P = 0.008). Among participants with the lowest or second tertile of LDL-C, PCSK9 quartiles were linearly associated with TPA (P = 0.021), but the association lost significance after additional adjustment for very low-density lipoprotein cholesterol (VLDL-C) tertiles (P = 0.072). Further stepwise linear regression (entry, 0.05; removal, 0.05) indicated that VLDL-C tertiles could be entered into the model but PCSK9 quartiles could not. Conclusions: Plasma PCSK9 levels are associated with 10-year progression of atherosclerosis. The LDL-independent association of PCSK9 levels may through its ability to regulate VLDL-C levels. Further research is needed to systematically investigate the role of PCSK9 for the pathogenesis of atherosclerosis, beyond LDL-C metabolism. (C) 2016 Elsevier Ireland Ltd. All rights reserved.