Hepatitis C virus (HCV) is responsible for most cases of chronic non-A, non-B hepatitis in multi-transfused children, but has been also implicated in at least one third of cases without history of parenteral exposure. We have recently evaluated the natural history of chronic hepatitis C in 37 children without underlying systemic diseases. None of the patients had a history of acute hepatitis and only 22 were symptomatic at presentation. Liver histology was consistent with active liver disease of mild to moderate activity in 42% of cases (one child had cirrhosis) and with persistent or lobular hepatitis in the remaining cases. During a mean follow-up period of 3.4 +/- 3.2 years symptoms were rarely observed and none of the patients developed liver failure, but 97% maintained abnormal alanine-aminotransferase levels. These results suggest that chronic hepatitis C in children, at least in its early stage, is a mild disease infrequently associated with severe liver lesions; however the persistence of liver damage over the years raises questions about the long-term outcome of the illness and about the rationale of antiviral therapy.