Abstract To understand the inter‐individual and virus‐independent variability of CD4 + T cell responses to HCV components, we evaluated the effect on these responses of HLA II molecules in uninfected healthy donors. Using HLA II‐specific binding assays, we identified, in the Core and NS3 proteins, 21 long fragments and 24 15‐mer peptides that bound to four to eight of the most preponderant HLA II molecules. We then evaluated the priming capacity of eight long promiscuous peptides in 12 HLA‐unrelated healthy donors. The NS3 1250–1264 peptide primed T cells in all the naive donors, while five others were stimulating in at least half of the individuals. We also report sequences that bind to multiple HLA II molecules but are weakly immunogenic. We therefore conclude that (i) broad HLA II specificity is only a prerequisite for a peptide to be stimulating in multiple individuals, and (ii) promiscuous peptides widely differ in their capacity to prime CD4 + T cells from uninfected healthy donors. We suggest that these priming differences result from inter‐individual variations in the peptide‐specific T cell repertoire. Interestingly, five of the most immunogenic peptides we identified correspond to frequently targeted T cell epitopes in infected patients.