Hepatitis B virus (HBV)-specific cytotoxic T lymphocytes (CTLs) can abolish HBV gene expression and replication through a noncytopathic mechanism mediated by tumor necrosis factor-alpha (TNF-alpha). However, the molecular mechanisms of TNF-alpha antiviral activity are not completely understood. To examine TNF-alpha-induced cellular responses and identify genes involved in anti-HBV activity, cDNA microarrays dotted with 14, 112 human genes were used to examine the transcriptional changes in HepG2 after treatment with TNF-alpha for 6 h. The results showed that many genes related to ligands and receptors, signal transduction including the TNF-alpha signaling pathway, mitochondrial and ribosomal proteins, and transcription regulation were induced by TNF-alpha. Interestingly, the TNF-alpha-inducible gene cIAP2 was found to inhibit HBV protein synthesis, viral replication, and transcription. Taken together, our results revealed the global effects of TNF-alpha treatment on hepatocellular gene expression. The antiviral genes identified by microarray could be developed as potential new anti-HBV drugs or for other novel therapies.