This study investigates the immune response during and after acute resolving hepatitis C virus (HCV) infection in three individuals. Using interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) and human histocompatibility leukocyte antigen (HLA) peptide tetramer assays, the researchers found that acute infection is associated with a broad T helper and cytotoxic T lymphocyte (CTL) response that persists after clinical hepatitis resolution and viremia clearance. At the earliest time point studied, highly activated CTL populations were observed that temporarily failed to secrete IFN-γ, a "stunned" phenotype, from which they recovered as viremia declined. In long-term HCV-seropositive individuals, CTL responses were more common in those who cleared viremia compared to those with persistent viremia, although the frequencies of HCV-specific CTLs were lower than those found in individuals during and after resolving acute HCV infection. These findings demonstrate a strong and persistent CTL response in resolving acute HCV infection and suggest that immune augmentation could be a therapeutic intervention for chronic HCV infection.This study investigates the immune response during and after acute resolving hepatitis C virus (HCV) infection in three individuals. Using interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) and human histocompatibility leukocyte antigen (HLA) peptide tetramer assays, the researchers found that acute infection is associated with a broad T helper and cytotoxic T lymphocyte (CTL) response that persists after clinical hepatitis resolution and viremia clearance. At the earliest time point studied, highly activated CTL populations were observed that temporarily failed to secrete IFN-γ, a "stunned" phenotype, from which they recovered as viremia declined. In long-term HCV-seropositive individuals, CTL responses were more common in those who cleared viremia compared to those with persistent viremia, although the frequencies of HCV-specific CTLs were lower than those found in individuals during and after resolving acute HCV infection. These findings demonstrate a strong and persistent CTL response in resolving acute HCV infection and suggest that immune augmentation could be a therapeutic intervention for chronic HCV infection.