Direct-acting antiviral has replaced pegylated interferon-α and ribavirin-based treatment in the treatment of chronic hepatitis C virus (HCV) infection. While interferon-α is immune modulating and causes lymphopenia, interferon-free regimens seem to be well-tolerated. This study aimed to compare T-cell homeostasis before, during, and after HCV treatment with or without interferon-α in patients with chronic HCV infection. A total of 20 patients with chronic HCV infection were treated with pegylated interferon-α and ribavirin, and six patients were treated with an interferon-free regimen. All patients were treated for a minimum of 12 weeks. Interferon-α treatment caused an increase in the density of the receptor for IL-7 (IL-7Rα) during treatment, while interferon-free regimens caused a decrease in IL-7Rα density. After a sustained viral response, proportions of IL-7Rα+ T cells and IL-7Rα density decreased compared to prior treatment values. Finally, a proportion of CD8+ effector memory was lower while proportion of apoptotic T cells was higher after sustained virologic response compared to prior treatment. Despite lymphopenia during interferon, alterations in T-cell homeostasis during treatment were relatively similar in patients receiving interferon-based treatment and in patients receiving interferon-free treatment, and alterations during and after treatment seem to illustrate a reduced need for high levels of T cells aimed at controlling infection.