Myeloid-derived suppressor cells (MDSCs) play an important role in impairing the function of T cells. We characterized MDSCs in two chronic hepatitis C (CHC) cohorts: a cross-sectional group that included 61 treatment-naive patients with CHC, 14 rapid virologic response (RVR) cases and 22 early virologic response (EVR) cases; and a longitudinal group of 13 cases of RVR and 10 cases of EVR after pegylated-interferon-α/ribavirin treatment for genotype 1b HCV infection. Liver samples from 32 CHC patients and six healthy controls were subjected to immunohistochemical analysis. MDSCs frequency in treatmentnaive CHC was significantly higher than in RVR, EVR, or healthy subjects and was positively correlated with HCV RNA. Patients infected with HCV genotype 2a had a significantly higher frequency of MDSCs than those infected with genotype 1b. Decreased T cell receptor (TCR) ζ expression on CD8+ T cells was significantly associated with an increased frequency of MDSCs in treatment-naive CHC patients and was restored by L-arginine treatment in vitro. Increased numbers of liver arginase-1+ cells were closely associated with the histological activity index in CHC. The TCR ζ chain was significantly downregulated on hepatic CD8+ T cells in CHC. During antiviral follow up, MDSCs frequency in peripheral blood mononuclear cells was directly correlated with the HCV RNA load in the plasma and inversely correlated with TCR ζ chain expression in CD8+ T cells in both RVR and EVR cases. Notably, the RVR group had a higher frequency of MDSCs at baseline than the EVR group. Collectively, this study provides evidence that MDSCs might be associated with HCV persistence and downregulation of CD8 ζ chain expression.