Cellular immune mechanisms, especially those mediated by CD8+ T cells, are important in the pathogenesis and control of viral infections. On the other hand, as shown for chronic lymphocytic choriomeningitis virus infection in the mouse, CD8+ T cells may not only hinder the elimination of a virus, but make the host unresponsive to a second viral infection. In hepatitis C virus (HCV) infections, at least 50% of the patients become chronically infected, despite the detection of HCV-specific CTL and a specific proliferative response to HCV Ags in PBL and in lymphocytes isolated from the liver. To better understand the immunopathologic mechanisms of CD8+ cells in vivo and to search for a potential treatment, we applied murine CD8 mAbs to a patient with therapy-resistant chronic HCV. A drastic reduction of CD8+ circulating lymphocytes, a reduction of CD8 molecule density, and complement fixation on CD8+ cells were observed. The reduction of CD8+ cells was compensated partially by an elevation of CD4+ cells. High concentrations of neutralizing human anti-mouse Abs were induced. After the Ab infusions, the CD4/CD8 ratio in peripheral blood increased from 1.6 to values of about 3 during therapy, and gradually decreased to 2.3 1 yr after the last mAb infusion. A continuing decrease of serum aminotransferases and clinical improvement was observed. Interestingly, after initiation of treatment, a significant proliferative response to HCV-specific Ags became measurable.