Background: The cardio-ankle vascular index (CAVI) is a physiological indicator of arterial elasticity. However, limited information regarding the clinical significance of the CAVI in patients with hypercholesterolemia is available. This cross-sectional study aimed to elucidate the clinical significance of the CAVI for the primary prevention of cardiovascular disease (CVD) among postmenopausal women with hypercholesterolemia. Methods: A total of 168 untreated postmenopausal hypercholesterolemic women (low-density lipoprotein cholesterol levels ≥ 140 mg/dL, mean age ± standard deviation, 63 ± 10 years) with no history of CVD events were enrolled. The CAVI was measured using commercial devices, after which, its relationships with various clinical parameters, such as carotid artery ultrasonography findings and CVD biomarkers, were examined. Results: A significant positive correlation was observed between the CAVI and maximum intima-media thickness of the common carotid artery (max-C-IMT), which was evaluated using carotid artery ultrasonography (r = 0.49, P < 0.001). Regarding CVD biomarkers, the CAVI was significantly correlated with estimated glomerular filtration rate (r = -0.18, P < 0.001), high-sensitivity C-reactive protein (r = 0.36, P < 0.001), whole blood passage time as a marker of blood rheology (r = 0.41, P < 0.001), and skin autofluorescence as a marker of advanced glycation end products in tissues (r = 0.46, P < 0.001), although no significant correlation was noted between serum lipid parameters and the CAVI. Multiple regression analysis identified max-C-IMT (β = 0.35, P < 0.001), whole blood passage time (β = 0.18, P = 0.007), skin autofluorescence (β = 0.17, P = 0.011), and age (β = 0.16, P = 0.018) as variables independently associated with CAVI. Conclusion: The present study indicated that the CAVI is an essential CVD risk factor among postmenopausal women with hypercholesterolemia. Moreover, impaired blood rheology and increase of skin autofluorescence were associated with elevated CAVI in such patients. J Clin Med Res. 2021;13(5):276-282 doi: https://doi.org/10.14740/jocmr4509