Chronic infection with the hepatitis C virus (HCV) is associated with failures of T-cell-mediated immune clearance and with abnormal B-cell growth and activation. We examined the levels of chemokines that bind to CXC chemokine receptor 3 (CXCR3) to determine whether such chemokines might play a role in the failure of the immune system to clear HCV infection. Elevations in CXC ligand 9 (CXCL9), CXCL10, and CXCL11 were observed in all patients with HCV. CXCR3 expression was increased significantly on peripheral blood B lymphocytes, but not T lymphocytes, from individuals with HCV infection. Chemokine levels were measured in samples collected before, during, and after antiviral therapy from a group of 29 patients infected with HCV genotypes 1a (24 patients) and 1b (5 patients). Levels of CXCL10 and CXCL9 decreased following successful antiviral therapy; CXCL11 did not decline significantly during or in the first 6 months after therapy. The baseline level of CXCL10 (measured before the start of antiviral treatment) was greatest in patients with HCV who subsequently became nonresponders to therapy. These results suggest that plasma concentrations of immunoreactive CXCL10 may be a predictor of responsiveness or nonresponsiveness to antiviral therapy with pegylated interferon (IFN) with or without ribavirin. This observation has implications for understanding the pathogenesis of HCV infection.