Hepatitis B virus (HBV) infection in children is worldwide in distribution, but the features of HBV-associated liver disease differ depending on the route of transmission and the time of acquisition of the infection. The degree of liver injury varies from a mild disease to the development of cirrhosis and hepatocellular carcinoma, and depends on the replicative status of the viral genome. It is believed that the immune function plays a key role in the severity of HBV disease, and the impact of HBV mutants needs to be assessed. The goals of antiviral therapy in children are therefore, the clearance of viremia and HBV sequences from infected tissues, together with an improvement in the liver disease. Administration of 10 MU/m2 b.s. 3 times weekly over 6 months resulted in a significantly higher clearance of viremia, with normalization of ALT values and greater improvement in liver histology in treated than in untreated patients. Long-term follow-up of these cases reveals the presence of the viral genome in serum and liver by PCR without clearance of HBsAg. Complete eradication of HBV might need more years of evolution as for adult patients. The combination of more than one antiviral agent, as well as the potentiation of the immune system, needs to be assessed to improve the actual response rate obtained with interferon-alpha.