Patients with recurrent hepatitis C after liver transplantation usually have a high viral load and are generally resistant to interferon (IFN)-α2b plus ribavirin (RBV) therapy. However, it remains unclear whether pretreatment viral titre determines the effectiveness of combination therapy, especially in patients with a high viral load. The aim of this study was to identify the viral factors associated with a sustained virological response (SVR) to antiviral therapy in patients with recurrent hepatitis C after living-donor liver transplantation. Twenty-three patients with recurrent hepatitis C received combination therapy of IFN-α2b plus RBV. SVR was achieved in 7 of the 23 patients (30.4%). Predictive factors for SVR included a 2 log10 decline in Hepatitis C virus (HCV) RNA at 2 weeks after the start of therapy and disappearance of HCV RNA at 4 or 24 weeks after the start of therapy. As the pretreatment high viral load showed no association with SVR, we asked whether other viral factor was associated with the response to the combination therapy in transplant recipients. We found the several novel defective HCV clones in 4 of 12 recipients' sera. All defective HCV clones had deletions in the envelope region. Interestingly, no patients with defective clones showed a prompt decrease in HCV RNA after the start of IFN-α2b plus RBV therapy. Thus, early decline in serum HCV RNA after treatment was closely associated with SVR. The circulating defective HCV clones are present and might be associated with the response to the combination therapy in patients with recurrent hepatitis after liver transplantation.