The SEN virus (SENV) is a recently identified single-stranded, circular DNA virus. A strong association between 2 SENV variants (SENV-D and SENV-H) and transfusion-associated non–A-to-E hepatitis has been reported. To clarify the effect of SENV infection on coexisting chronic hepatitis C and the effect of interferon alfa (IFN-α) therapy on SENV replication, SENV DNA was quantitated by polymerase chain reaction in serum samples from 186 patients with chronic hepatitis C. Thirty-nine of 186 (21%) patients with chronic hepatitis C were positive for SENV DNA. There were no differences in the clinical, virologic and histologic features between patients with and without SENV infection. Eighteen of 102 patients with chronic hepatitis C who received IFN-α were positive for SENV DNA. The sustained response rate for hepatitis C virus (HCV) clearance after IFN-α treatment did not differ significantly between patients with SENV (28%) and without SENV infection (39%). SENV DNA levels decreased during therapy in 15 of 16 patients, and 11 of the 16 patients (69%) had a sustained loss of SENV DNA in response to IFN-α. In coinfected patients, SENV responses to IFN-α were significantly better in those who failed to clear HCV RNA than in those who lost HCV RNA (P = .013). In conclusion, SENV infection was frequently found in patients with chronic hepatitis C. SENV infection had no apparent influence on the severity of HCV-related liver disease or the HCV response to IFN-α. SENV was sensitive to IFN-α therapy and the majority of patients had a sustained virologic response.