The hepatitis C virus (HCV) core protein is considered to influence multiple cellular processes. We developed a human hepatoblastoma HepG2-derived inducible cell line, Hep191, which allows tightly regulated expression of the core protein at relatively low but physiological levels under control of the ecdysone-regulated promoter. By transcriptional profiling, we identified differentially expressed genes, some of which are involved in cell growth or apoptosis such as inhibitor of caspase-activated DNase (ICAD), defender against cell death 1, tumor necrosis factor (TNF) receptor 1, and cytochrome c oxidase subunit VIII. Furthermore, we found that core protein expression increases a steady-state level of ICAD protein, possibly through enhancing its promoter activity, and inhibits caspase-3 activity induced by anti-Fas antibody. Since Fas- or TNF-mediated DNA fragmentation is suppressed in the core-induced Hep191 cells, these findings suggest that expression of HCV core at physiological levels confers blocking activity of caspase-activated DNase and consequently inhibiting apoptotic cell death.