Neutralizing antibodies and cellular immune response both play essential roles in the clearance of Hepatitis C virus (HCV) infection. The envelope glycoprotein E2 is a major target for producing neutralizing antibodies against HCV. Here, we constructed a recombinant plasmid, termed pcDNA3.1-E2-Fc, to express HCV E2 with an immunoglobulin Fc fusion tag (E2-Fc). Importantly, we found that the titers of E2-specific IgG from mice immunized with pcDNA3.1-E2-Fc were significantly higher than that from mice immunized with pcDNA3.1-E2. Moreover, pcDNA3.1-E2-Fc immunization could boost E2-specific lymphocyte proliferation and enhance the secretion of IFN-γ by lymphocytes upon in vitro stimulation with soluble E2 compared to pcDNA3.1-E2 immunization. Neutralization assays showed that serum from pcDNA3.1-E2-Fc immunized mice exhibited more effective neutralizing capacity of HCVpp entry into Huh-7 cells compared with that from pcDNA3.1-E2 immunized mice, although both of the sera could inhibit the virus entry. Taken together, our results imply that pcDNA3.1-E2-Fc immunization could enhance E2-specific humoral and cellular immune response in mice and thus provide a promising candidate for the development of an HCV vaccine. J. Med. Virol. 87:2090–2097, 2015. © 2015 Wiley Periodicals, Inc.