The role of hepatitis C virus (HCV) infection in the development of vascular disease is controversial. Insulin resistance (IR) is a recognized risk factor for cardiovascular disease (CVD) and is associated with chronic hepatitis C (CHC) infection. Thus, IR may promote atherosclerosis and vascular disease in CHC patients. HCV-associated IR may also cause hepatic steatosis and resistance to antiviral treatment. In addition, HCV may impose direct, proatherogenetic action in the vascular wall. This review will elaborate the impact of IR on interferon-α based therapy of HCV infection and the role of insulin-sensitizing agents on the response to antiviral treatment and prevention of IR complications, including vascular disease.