AbstractProtease proprotein convertase subtilisin/kexin type 9 (PCSK9) is a regulator of LDL cholesterol clearance and has been associated with cardiovascular risk. PCSK9 inhibitors increase in vivo circulating endothelial progenitor cells (EPCs), a subtype of immature cells involved in ongoing endothelial repair. We hypothesized that the effect of PCSK9 on vascular homeostasis may be mediated by EPCs in patients with or without type 2 diabetes mellitus (T2DM). Eighty-two patients (45 with, 37 without T2DM) at high cardiovascular risk were enrolled in this observational study. Statin treatment was associated with higher circulating levels of PCSK9 in patients with and without T2DM (p < 0.001 and p = 0.036) and with reduced CD45^neg/CD34^bright (total EPC compartment) (p = 0.016) and CD45^neg/CD34^bright/CD146^neg (early EPC) (p = 0.040) only among patients with T2DM. In the whole group of patients, statin treatment was the only independent predictor of low number of CD45^neg/CD34^bright (β = − 0.230; p = 0.038, adjusted R² = 0.041). Among T2DM patients, PCSK9 circulating levels were inversely related and predicted both the number of CD45^neg/CD34^bright (β = − 0.438; p = 0.003, adjusted R² = 0.173), and CD45^neg/CD34^bright/CD146^neg (β = − 0.458; p = 0.002, adjusted R² = 0.191) independently of age, gender, BMI and statin treatment. In high-risk T2DM patients, high endogenous levels of PCSK9 may have a detrimental effect on EPCs by reducing the endothelial repair and worsening the progression of atherothrombosis.