The impact of naïve-precursor frequency on human virus-specific CD8(+) T cell immunodominance is not well understood. Using a recently developed major histocompatibility complex (MHC) class I tetramer enrichment protocol, we found a conserved hierarchy and a >10-fold difference in naïve-precursor frequencies across three HLA-A2-restricted hepatitis C virus (HCV)-specific epitopes. Importantly, the NS3(1406) epitope with the highest naïve-precursor frequency in healthy donors was also the most frequently targeted epitope in a large cohort of chronically HCV-infected patients, both ex vivo and after in vitro stimulation. These results indicate for the first time that immunodominance in a human viral infection is linked to naïve-precursor frequency.