Chronic infection with hepatitis B virus (HBV) is associated with an increased risk for the development of cirrhosis and hepatocellular carcinoma (HCC).C hronic hepatitis B virus (HBV) infection is one of the major etiologic factors in the development of hepatocellular carcinoma (HCC). 1,2 Epidemiologic studies have shown that chronic HBV-infection is associated with a 100-fold increase in the risk for HCC development relative to noncarriers, placing HBV in the forefront among known human carcinogens. 3,4 Several lines of evidence suggest that HBV is tolerated by infected hepatocytes that do not show overt pathogenic reactions to virus replication. Therefore, liver damage observed in acute or chronic hepatitis B infection is mainly caused by cellular immune responses, which play a key role in the control of HBV infection. 5 Continuous necrosis and liver cell regeneration in the inflammatory context provide the driving force for carcinogenic progression in HBV carrier livers by allowing the selection of mutated hepatocytes. The long latency period for the development of HCC reveals a multistaged mechanism, in which selection of progressively mutated hepatocytes occurs. Moreover, virus-host interactions have been related to the oncogenic properties of the virus. Tumor progression may also be promoted by the presence of viral gene products, such as the X protein, 6-8 or by overexpression and accumulation of the large envelope protein. 9 The inappropriate expression of a truncated form of the middle envelope protein produced from integrated viral sequences has also been reported. 10 A direct role for integration of a mammalian hepadnavirus in the development of HCC has been identified for the woodchuck hepatitis virus (WHV). Integrations of WHV DNA into the N-myc and c-myc protooncogenes have shown that WHV integration can activate cellular protooncogenes by enhancer or promoter insertion. 11,12 Molecular analysis of genomic DNA from human HCCs revealed the presence of clonally propagated viral DNA integrations and the majority of tumors from chronic HBV carriers harbor integrated viral DNA, often multiple copies per cell. [13][14][15][16] Although a cellular protooncogene that is commonly activated by HBV has not been identified, the high prevalence of HBV integrations at sites of chromosomal abnormalities, such as deletions, duplications, and chromosomal translocations, has suggested that the integration process may occur in a manner that promotes mutagenesis. 1,17,18 Studies on the natural history of integrations of duck hepatitis B virus (DHBV) have directly shown that hepadnavirus integrations