With advances in tools for the diagnosis of hepatitis C virus (HCV) infection, it has become easier to evaluate the natural course of hepatitis C. Although HCV infection initially occurs in adult individuals, in most patients with acute hepatitis C (68%) it develops into chronic hepatitis. Once chronic hepatitis is established, the rate of spontaneous cure of the liver disease is very rare (below 2%). The duration from the onset of acute hepatitis until the time of diagnosis of cirrhosis of the liver and of hepatocellular carcinoma is about 20 and 30 years, respectively. The long-term clinical course of hepatitis C is divided into the three phases of acute, silent, and reactivated. The acute phase lasts from the onset of disease until 2-3 years thereafter, and the silent phase which follows lasts for 10-15 years. In the silent phase, the serum transferase level remains relatively low, below 100 IU/l, and is sometimes within the normal range. In the reactivated phase, the level of serum aminotransferase increases and remains at a high or moderate level until hepatocellular carcinoma develops. The mechanism of the chronicity of hepatitis C is unknown. However, recent advances in molecular analysis may soon elucidate this. Successive antigenic change of the HCV E2/NS1 hypervariable domain as a result of mutations may represent a mechanism by which this virus escapes the host immunosurveillance system, as well as a mechanism of its chronicity.