Hepatocellular carcinoma (HCC) is a fatal disease and hepatitis B and C viruses (HBV and HCV) are considered as major causative factors for the development of HCC. We have conducted gene expression profiling studies to search for potential target genes responsible for HCV-mediated HCC. Adenoviruses encoding core (HCV structural protein), NS3 and NS5A [HCV non-structural (NS) proteins] were generated and infected individually or together in freshly isolated primary human hepatocytes. An adenovirus harboring the oncogenic HBV protein, HBx, was included for comparison. A microarray platform of over 22,000 human oligos was analyzed to seek out significant differentially expressed genes among these viral proteins. We also compared these gene expression profiles with those obtained from HCV-infected liver samples from chronic liver disease (CLD) patients and HCV-related HCC. We found that HCV-related proteins largely induce unique genes when compared with HBx. In particular, interferon-inducible gene 27 (IFI27) was highly expressed in HCV or core-infected hepatocytes and HCV-related CLD or HCC, but was not significantly expressed in HBx-infected hepatocytes or HBV-related CLD or HCC, indicating that IFI27 may play a role in HCV-mediated HCC. In conclusion, our results suggest that HBV and HCV promote HCC development mainly through different mechanisms.