Hepatitis C Virus (HCV) is a single stranded RNA virus causing non-A and non-B hepatitis. Core protein is a viral capsid protein that plays an important role in the pathogenesis of HCV. The companion report revealed that an innate form (amino acids [a.a.] 1-191) regulated subcellular localization of a mature form (a.a. 1-173). It was also shown that the innate form in the cytoplasm enhanced the p21 expression and the mature form in the nucleus suppressed the p21 expression. Here we report that the core protein in the cytoplasm increases the amount of p21 via activating p53, and the core protein in the nucleus decreases the amount of p21 by the p53-independent pathway. These observations suggest that the regulation of p21 expression by the core protein via subcellular localization might decide the fate of infected cells either to the proliferation or to the apoptosis.