Introduction: One unusual characteristic of HCV is to establish chronic infection and the precise mechanisms remain unclear. Materials and methods: Huh-7 cells were transiently transfected with E2 and subjected to MTT assay, DNA fragmentation assay, and Western blotting to see the impact of E2 protein on apoptosis. Results and discussion: E2 may inhibit cell proliferation by inducing apoptosis and pro-caspases 3, 8. and 9 were cleaved and activated to result in the presence of active forms in a time-dependent fashion, which suggest that E2-induced apoptosis is caspase-dependent. Furthermore, the cytosolic level of cytochrome c was increased together with a gradually down-regulated Bcl-2 and up-regulated Bax protein expression. The continuing reduction of Bid protein and the gradual increase of tBid protein also indicated that a time-dependent increased turn-over of Bid protein into tBid. Taken together, our data suggested that HCV E2 may induce apoptosis through a mitochondrial damage-mediated caspase pathway. (c) 2006 Elsevier Inc. All rights reserved.