A hepatoblastoma cell line transfected with hepatitis B virus (HBV) DNA (Hep G2.2.15) was used to investigate the effects of interferons (IFNs) on HBV replication and hepatocellular gene expression. IFN-α2b or -β inhibited HBV replication transiently. In parallel, there was a decrease in the amount of HBV mRNA. Hepatitis B surface antigen and early antigen secretion were not influenced; however, their intracellular levels diminished during treatment. The cellular 2′,5′-oligoadenylate synthetase activity was increased 9- to 18-fold during treatment of cells with IFN-γ, -α, or -β. The number of IFN-α and -β receptors was down-regulated, while the number of IFN-γ receptors remained constant. The expression of major histocompatibility complex class I antigens was stimulated by addition of IFN-α or -β. These data show that both IFN-α and -β can effectively inhibit HBV replication and induce a cellular IFN response in Hep G2.2.15 cells similar to that seen in humans.