To investigate responses of hepatitis C virus (HCV) and TT virus (TTV) to high dose and long duration interferon-alpha (IFN-alpha) therapy (540 million units in 36 weeks) and factors associated with the viral clearance, sera of 165 Taiwanese naïve chronic hepatitis C patients were tested for alanine aminotransferase, HCV RNA levels, HCV genotypes and TTV DNA. With 41.8% of TTV DNA prevalence, TTV viremia was significantly associated with history of blood transfusion (P<0.01). After IFN therapy, HCV complete response was achieved in 60 (36.4%) patients and significantly associated with lower pretreatment levels of HCV RNA (P<0.01) and HCV genotype non-1b (P<0.05). Fifty-three patients with concurrent TTV infection were evaluated for TTV response. TTV sustained clearance was achieved in 24 (48%) patients and significantly associated with loss of TTV DNA at the end point of treatment. In conclusion, concurrent TTV infection is highly prevalent, related to blood transfusion and independent of HCV infection. After high dose and long duration IFN-alpha therapy, HCV and TTV clearance are achieved among more than one-third and around one-half patients. HCV RNA levels and HCV genotypes are predictors for HCV response and no clinical factors are observed to be associated with TTV clearance.