Nowadays, hepatitis C infection has been identified as the main cause of chronic liver disease, including cirrhosis and hepatocellular carcinoma in Western Countries. However, despite its large diffusion (with more than 150 million of people infected world-wide), the lack of symptoms during the acute phase, together with the indolent course of the disease over time, hampers the difficulties to assess the natural history of the disease, which still remains an interesting clinical dilemma. This complexity can also be argued from the large heterogeneity of disease complication's rate observed when different methodological approaches were used (retrospective cohort studies, prospective cohort studies, retrospective-prospective cohort studies). Moreover, the progression of the disease could also be dramatically affected by many variables related to the host, the virus and the environment. Finally, in the last few years, the long-term outcome of the infected subjects, has been deeply modified by the use of efficacy antiviral therapy, as shown by the better survival observed in patients who had achieved a sustained virological response after interferon treatment.