AIM: To characterize the IFN-response and its modulation by the antiviral compound lamivudine in HBVtransfected HepG2.2.15 cells.METHODS: HepG2.2.15 and HepG2 cells were stimulated with various concentrations of IFN-α2a in the presence or absence of lamivudine. Then, total RNA was extracted and analysed by customised cDNA arrays and northern blot for interferon-inducible genes (ISGs). In addition, cellular proteins were extracted for EMSA and western blot. HBV replication was assessed by southern blot or ELISAs for HBsAg and HBeAg.RESULTS: Two genes (MxA, Cig5) with completely abolished and 4 genes (IFITM1, -2, -3, and 6-16)with partially reduced IFN-responses were identified in HepG2.2.15 cells. In 2 genes (IFITM1, 6-16), the response to IFN-α could be restored by treatment with lamivudine. This effect could not be explained by a direct modulation of the Jak/Stat signalling pathway since EMSA and western blot experiments revealed no suppression of Stat1 activation and ISGF3 formation after stimulation with IFN-α in HepG2.2.15 compared to HepG2 cells.CONCLUSION: These results are consistent with the assumption that chronic hepatitis B may specifically modulate the cellular response to IFN by a selective blockage of some ISGs. Antiviral treatment with lamivudine may partially restore ISG expression by reducing HBV gene expression and replication.