S. Nakamoto 1 , F. Imazeki 1 , K. Background/Aims: Recently amino acid (aa) substitutions in hepatitis C virus (HCV) core region (double wild (DW); arginine at aa 70, leucine at aa 91) were reported to be associated with sustained virological response (SVR) in a combination therapy of peginterferon and ribavirin. We evaluated the viral factors influencing treatment response. Methods: Nucleotide sequences of core region were determined directly in 104 patients with genotype 1 and high viral load ( 100 KIU/ml) treated with peginterferon-alpha 2b and ribavirin for 48 weeks. Rapid virologcal response (RVR) was defined as more than 2 log decrease of HCV-RNA during the first four weeks of therapy and early virological response (EVR) as that during the first 12 weeks. SVR was defined as negative HCV-RNA 6 months after the end of treatment and non-virological response (NVR) as less than 2 log decrease of HCV-RNA during the treatment. Results: DW at aa 70 and 91 was shown in 17/44 (35%) patients with RVR and in 5/44 (11%) with non-RVR (p=0.003), in 25/72 (35%) with EVR and in 1/28 (3.6%) with non-EVR (p=0.001), in 16/37 (43%) with SVR and in 6/44 (14%) with non-SVR (p=0.003), and in 1/24 (4%) with NVR and in 25/79 (32%) with non-NVR (p= 0.005). In multiple logistic regression analysis, DW was significantly associated with RVR, EVR, SVR and NVR. Conclusions: DW at aa 70 and 91 in HCV core region was closely associated with virological response in a combination therapy of peginterferon and ribavirin. Medicine and Hepatology, Henry Dunant Hospital, Athens, Greece, 3 Biometrics, IST GmbH, Mannheim, Germany, 4 