The natural history of chronic hepatitis C has been defined in several retrospective and prospective studies conducted in the last 20 years. These studies have clearly demonstrated that the outcome of chronic hepatitis C virus infection is profoundly influenced by a variety of cofactors and comorbidities. Many of the cofactors that affect the course of liver disease in hepatitis C also have a significant influence on the result of antiviral therapy. Unfortunately, comorbidities that have been shown to negatively influence the course and outcome of liver disease often reduce the chance of achieving a sustained virological response with pegylated interferon (PEG-IFN) and ribavirin treatment. The most important and frequent comorbidity influencing the course of chronic hepatitis C and the response to antiviral therapy is represented by the metabolic syndrome, and by the associated state of insulin resistance. Other comorbidities that have a negative influence on the progression of hepatitis C and on the response to antiviral therapy include excess alcohol intake, human immunodeficiency virus and hepatitis B virus co-infection and a number of conditions that reduce the benefit of therapy by affecting negatively compliance and/or adherence to adequate PEG-IFN or ribavirin doses.