Abstract The majority of acute hepatitis C virus (HCV) infection (75%) leads to chronicity and liver diseases. While 25% of infected individuals can naturally clear the infection, long-term protection is elusive and reinfection can occur. We have previously showed that protection from viral persistence upon HCV reinfection correlates with expansion of HCV specific T cells with increased breadth. Viral persistence was associated with limited expansion of virus specific T cells. CD8 T cell receptor (TCR) repertoire analysis showed that clonotypes associated with protection upon reinfection are recruited from the memory population, with focusing of the repertoire. We hypothesized that protective immune memory response is associated with selection of T cell clonotypes with the highest TCR avidity and a polyfunctional profile. We FACS sorted HCV-specific CD8 T cells to generate individual clones representative of clonotypes of high, medium or low frequency in the TCR repertoire. Tetramer titration assay showed that the TCR avidity correlated with the clonotype expansion in vivo upon reinfection. All clones showed a polyfunctional profile but the main function varied between clones. In conclusion, our results suggest that the main determinant for the expansion of memory HCV specific CD8+ T cells during HCV reinfection was the TCR avidity. The results of this study have implications for the development of vaccination regimens to boost generation and selection of such clonotypes.