Members of the hepadnavirus family share properties of virion structure, genome structure and replication, epidemiologic behavior, and pathogenic effects. Persistent infections with hepatitis B virus (HBV) in man, woodchuck hepatitis virus (WHV) in Marmota monax, ground squirrel hepatitis virus (GSHV) in Spermophilus beecheyi, and duck hepatitis B virus (DHBV) in domestic ducks of China are associated with development of hepatocellular carcinoma (HCC). Epidemiological evidence implicating hepadnavirus infection in HCC includes the observation that the geographic distributions of HBV infection and HCC are similar, that the incidence of HCC is much higher in hepadnavirus-infected than uninfected hosts, and that viral DNA sequences are integrated in the cellular DNA of most (e.g., 80 to 90%), but not all, hepadnavirus-associated HCC. Cirrhosis further increases the risk of HCC in HBV-infected humans. The precise role of hepadnaviruses in development of most HCC is unclear, although the finding of viral integrations within or near protooncogenes in a few cases suggests the possibility that these integrations may play a direct role in these HCC. However, in the great majority of HCC, viral integrations are in different cellular DNA sites in different HCC, integrations are not within domains of known protooncogenes, and integrations are not found in some 10 to 15% hepadnavirus-associated HCC, suggesting that persisting viral sequences are not directly involved in the development of these HCC as viral sequences are for tumors caused by viruses with oncogenes or viruses that act by a "promoter-insertion" mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)