Background: Hepatitis C virus has been linked to increased prevalence of type 2 diabetes mellitus, both in cross-sectional and longitudinal studies. Indeed, insulin resistance and type 2 diabetes was more often seen in hepatitis C than others liver diseases and was associated with higher fibrosis progression rate. Besides, insulin resistance impairs hepatitis C cure rate after peginterferon plus ribavirin standard combination therapy (SOC). Results: A novel rationale for the management of hepatitis C could target on the treatment of insulin resistance. Data are available from a randomized, double-blinded, placebo-controlled trial including 123 patients with genotype 1 and insulin resistance. Patients were allocated to receive either metformin or placebo in addition to peginterferon alfa-2a (180 µg/week) and ribavirin (1000-1200 mg/d). Metformin improved sustained virological response (SVR) in females and patients that reached HOMA lower than 2 at week 24. However, Pioglitazone, in pilot trials, improved early virologic kinetics and the end-of-treatment response, but not SVR.