The induction of virus-specific cytotoxic T lymphocytes (CTL) is an important part of vaccine strategy. CTL induction in vivo by two hepatitis C virus (HCV) peptides containing CTL epitopes, one from the NSS region (P17) and one from the core (C7), was compared. Pl7 required covalent attachment of a helper peptide (PCLUS3 containing a cluster of epitopes from the human immunodeficiency virus envelope protein), whereas C7 did not. However, the minimal decapeptide of C7, C7A10, alone did not induce CTL. The helper cells induced by PCLUS3-17 or by C7 were shown to be CD4⁺ and to produce interleukin-2 (IL-2). Thus, help can be supplied by a natural helper epitope intrinsic to the CTL peptide, as in C7, or by attaching a helper epitope from another protein, as in the case of P17. The cluster peptides may be useful promiscuous helper peptides for a variety of CTL epitopes from diverse pathogens.