Several evidences reported the involvement of a class of cysteine proteases in the pathogenesis of cardiovascular diseases (CVD). In particular, high Cathepsin K (CatK) concentrations have been found in atherosclerotic lesions. Furthermore, CatK ablation in a murine model ameliorated diabetes-induced hyperglycemia, alterations in energy metabolism, and cardiovascular structural/functional abnormalities. However, the involvement of CatK in cardiovascular complications associated with diabetes and the potential molecular mechanisms involved have not been elucidated yet. To address this issue, we analyzed the serum CatK levels in 551 well-characterized subjects. We evaluated the clinical utility of measuring CatK in assessing subclinical cardiovascular organ damage defined by carotid artery intima-media thickness (c-IMT) and left ventricular mass index (LVMI). The comparison of normal-glucose tolerance (NGT), prediabetes and T2DM groups evidenced a significant increment of circulating CatK levels with T2DM individuals showing higher mean values (2.43±0.97ng/ml) compared to NGT and prediabetes (1.15±0.52 and 1.22±0.33ng/ml, respectively). After correction for age, sex and BMI, circulating CatK levels were positively correlated with triglycerides (r=0.088, p=0.041), fasting glucose levels (r=0.316; p<0.001), fasting insulin levels (r=0.268; p<0.001), HOMA-IR (r=0.336; p<0.001), HbA1c (r=0.376; p<0.001), c-IMT measures (r=0.213; p<0.001) and LVMI in the female subset of the population (r=0.217; p<0.01). No significant correlation was observed between CatK and LVMI in the male subset. To estimate the independent contribution of CatK levels to c-IMT in T2DM patients, a multiple linear regression analysis was performed. Age (β=0.287; p<0.001), sex (β=0.209; p=0.003), and CatK concentration (β=0.160; p=0.022) were resulted significantly associated with c-IMT in the T2DM group. Comparison of standardized coefficients allowed to determine the relative impact of each factor on LVMI. Age (β=0.392; p<0.001) and CatK (β=0.208; p=0.046) were significantly associated with LVMI in women. Our data confirm that CatK circulating levels are positively correlated with c-IMT and LVMI in the diabetic population, indicating that CatK may play a role in the early etiopathogenesis of CVD complications in T2DM.