Hepatitis C virus core (HCVcore) protein was expressed in myeloid dendritic cells (DC) from C57/B6 mice (H-2K(b)) by electroporation of HCVcore mRNA to investigate its effect on the ability of DC to prime CD8+ T cells displaying a T cell receptor specific for OVA(257-264) peptide (SIINFEKL)/H-2K(b) complex. Expression of full length HCVcore(191), which is directed to the endoplasmic reticulum (ER) membrane by a C-terminal signal sequence, but not a truncated variant HCVcore(152), which has a wider subcellular localization including the nucleus, significantly reduced surface levels of the H-2K(b)/SIINFEKL complex and impaired the ability of DC to prime naïve CD8+ T cells when they had to process endogenous antigen but not when MHC class I molecules were loaded directly with SIINFEKL peptide. Exploitation of the MHC class I antigen-processing pathway by HCVcore(191) impairs the ability of DC to stimulate CD8+ T cells and may contribute to the persistence of HCV infection.