The natural history of chronic Hepatitis C Virus (HCV) infection is still poorly understood. The main reason is the asymptomatic onset and course in the majority of infected subjects. Moreover, in the presence of the very effective therapies now available it is impossible to follow people untreated in order to analyse the events and their timing and type of evolution. For these reasons, most studies are mainly retrospective, although studies on post-transfusion hepatitis could help in understanding the natural course of the infection. Another important phenomenon that makes this issue problematic is that chronic HCV infection is not linear in time, probably because many co-factors can change the speed of development of fibrosis, cirrhosis and hepatocellular carcinoma. Data now available show that this disease can persist for about two decades with limited morbidity and mortality; problems may arise between the third and fourth decade after infection. Alcohol consumption is a very important factor of additional risk of progression, but there are several other factors (iron, steatosis, metabolic problems, etc.) that must be better analysed. In conclusion, only in a small group (no more than 15%) of all HCV-infected patients does the disease reduce quality and/or quantity of life.