Steatosis, or "fatty liver", is a common finding in Hepatitis C virus (HCV) infection and reflects dysregulation of lipid homeostasis. HCV Core protein causes lipid accumulation when expressed in cultured cell lines, which data now indicates is a critical step for HCV replication, assembly and release. Previous studies on HCV Core and lipid accumulation have been limited by poor efficiency of conventional transfection techniques or the cell line limitations of the available cell culture system. In this study, we have designed recombinant adenoviruses expressing HCV Core and demonstrate that infection of both cultured and primary cells leads to intracellular lipid accumulation. This system will allow for detailed studies of the mechanisms that drive intracellular lipid accumulation during HCV infection and addresses some of the disadvantages that have hampered previous research.