AIM: The clinical significance of co-infection of SENV-D among patients with chronic hepatitis C (CHC) and response of both viruses to combination therapy with high-dose interferon-alfa (IFN) plus ribavirin remain uncertain and are being investigated.METHODS: Total 164 (97 males and 67 females, the mean age 48.1±11.4 years, range: 20-73 years, 128histologically proved) naive CHC patients were enrolled in this study. SENV-D DNA was tested by PCR method.Detection of serum HCV RNA was performed using a standardized automated qualitative RT-PCR assay (COBAS AMPLICOR HCV Test, version 2.0). HCV genotypes 1a,1b, 2a, 2b, and 3a were determined by using genotypespecific primers. Pretreatment HCV RNA levels were determined by using the branched DNA assay (Quantiplex HCV RNA 3.0). There are 156 patients receiving combination therapy with IFN 6 MU plus ribavirin for 24 wk and the response to therapy is determined.RESULTS: Sixty-one (37.2%) patients were positive for SENV-D DNA and had higher mean age than those who were negative (50.7±10.6 years vs46.6±11.6 years,P = 0.026). The rate of sustained viral response (SVR)for HCV and SENV-D were 67.3% (105/156) and 56.3%(27/48), respectively. By univariate analysis, the higher rate of SVR was significantly related to HCV genotype non-1b (P＜0.001), younger ages (P = 0.014), lower pretreatment levels of HCV RNA (P = 0.019) and higher histological activity index (HAI) score for intralobular regeneration and focal necrosis (P = 0.037). By multivariate analyses, HCV genotype non-1b, younger age and lower pretreatment HCV RNA levels were significantly associated with HCV SVR (odds ratio (OR)/95% confidence interval (CI): 12.098/0.02-0.19, 0.936/0.890-0.998, and 3.131/1.080-9.077, respectively). The SVR of SENV-D was higher among patients clearing SENV-D than those who had viremia at the end of therapy (P = 0.04).CONCLUSION: Coexistent SENV-D infection, apparently associated with higher ages, is found in more than onethird Taiwanese CHC patients. Both HCV and SENV-D are highly susceptible to combination therapy with high-dose IFN and ribavirin and SENV-D co-infection does not affect the HCV response. HCV genotype, pretreatment HCV RNA levels and age are predictive factors for HCV SVR.