Chronic hepatitis HCV-related is the most common cause of chronic liver disease in Italy. Patients with chronic hepatitis C present a prevalence of depressive disorders higher than that of the general population; moreover, it has been repeatedly demonstrated the presence of cognitive deficits and poor quality of life. Chronic hepatitis C therapy was based on the combined use of pegylated alpha-interferons (PEG-INF), and ribavirin. Recently, new therapeutic protocols have been introduced, and while some antiviral drugs, including the first-generation ones, were used only in combination with PEG-IFN and ribavirin, the second and third generation antiviral drugs protocols are interferon-free. However, because of the high cost, the access to interferon-free protocols is only for patients with advanced fibrous stages, or with concomitant extra-hepatic HCV-related diseases, or for transplanted patients. Many side effects, such as flu-like symptoms, and psychiatric symptoms (depression, anxiety, irritability, insomnia) are common during antiviral therapy with IFN. However, in patients with chronic hepatitis C, a high lifetime prevalence of major depressive disorder, panic disorder, and brief recurrent depression have been observed, irrespective of IFN treatment and the use of alcohol and narcotics; such associations between mood and anxiety disorders and chronic hepatitis C may reflect a high prevalence of bipolar spectrum disorders. The presence of severe psychopathological symptoms requires the reduction of posology and causes high rates of discontinuation of antiviral therapy.