During chronic liver disease (CLD), angiogenesis participates in the fibrogenic process. Herein, we aimed at verifying the on-treatment kinetics of serum vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) in hepatitis C virus (HCV) patients undergoing antiviral therapy. Forty-three HCV patients treated with pegylated-interferon/ribavirin and 26 controls were studied. Serum VEGF and Ang-2 were determined before treatment, at different time points during treatment, and at follow-up after treatment. Thirty and 13 patients were sustained virological responder (SVR) and No-SVR, respectively. Patients showed increased Ang-2 levels [504 (368-720) versus 449 (389-483) pg/mL, P < 0.05], and equivalent VEGF levels [271 (193-377) versus 274 (199-324) pg/mL, P = 0.6], with respect to controls. By univariate analysis, stage of fibrosis was associated with Ang-2 levels (odds ratio 4.25, P < 0.05). In SVR patients VEGF levels showed a progressive reduction (P < 0.05) but returned to pretherapy levels at follow-up, and Ang-2 levels showed an opposite progressive increase, being significantly reduced at follow-up (P < 0.01). No significant modifications in VEGF and Ang-2 levels were observed in No-SVR. We conclude that, in patients with HCV-CLD, Ang-2 serum levels are associated with fibrosis and reduced at follow-up in SVR patients. On-treatment, VEGF and Ang-2 serum levels undergo different-sided modifications only in SVR patients, possibly expressing the vascular remodeling occurring early after viral clearance.