We describe a peptide-based strategy for hepatitis C virus (HCV) vaccine design that exploits synthetic peptides representing antibody epitopes of the hypervariable region 1 (HVR1) of the E2 glycoprotein and also less variable regions immediately downstream of HVR1. These epitopes were linked to a T-helper (T(h)) epitope (KLIPNASLIENCTKAEL) derived from the Morbillivirus canine distemper virus. Antibody titres induced by the two vaccine candidates T(h)-A (E2 amino acid 384-414) and T(h)-B (E2 amino acid 390-414) were significantly higher than those produced against vaccines lacking the T(h) epitope (P<0.05). Mice inoculated with the vaccine candidates T(h)-C (E2 amino acids 412-423) and T(h)-F (E2 amino acids 436-447) emulsified in complete Freund's adjuvant each elicited antibody titres that were significantly higher than those elicited by T(h)-E (E2 amino acids 396-407) and T(h)-D (E2 amino acids 432-443) (P<0.01). Antisera obtained from mice inoculated with the epitope vaccines T(h)-A, T(h)-B, T(h)-D and T(h)-E bound to E2 expressed at the surface of 293T cells that had been transfected with E1E2. Furthermore, IgG from the sera of mice inoculated with four of the vaccine candidates, T(h)-A, T(h)-C, T(h)-D and T(h)-E, inhibited the entry of HCV/human immunodeficiency virus pseudoparticles (HCVpps) into Huh-7 cells. These results demonstrate the potential of synthetic peptide-based constructs in the delivery of potential neutralizing epitopes that are present within the viral envelope of HCV.