GB virus C/hepatitis G virus (GBV-C/HGV) infection seems to be common among patients with hepatitis C virus (HCV) infection. We studied retrospectively the proportions of patients with GBV-C/HGV RNA and antibodies to the GBV-C/HGV second envelope protein (anti-E2) among 149 subjects with chronic hepatitis C who had received interferon alfa. The clinical characteristics of patients with GBV-C/HGV RNA or anti-E2 were examined, as was the efficacy of the treatment. Stored serum specimens were tested for GBV-C/HGV RNA by the reverse transcription polymerase chain reaction and for anti-E2 by an enzyme-linked immunosorbent assay. Of the 149 patients before therapy, 8 (5%) had GBV-C/HGV RNA only, 72 (48%) had anti-E2 only, and 4 (3%) had both. The mean age of patients with GBV-C/HGV RNA (some with anti-E2) was significantly less than that of patients with anti-E2 only. Results of laboratory and histological evaluations were not different depending on the presence of GBV-C/HGV RNA or anti-E2. The GBV-C/HGV RNA titer decreased during therapy in all 12 patients with GBV-C/HGV RNA; only 4, with a low titer before therapy and with anti-E2 detected at some time, had sustained clearance of GBV-C/HGV. Our results suggested that half of the patients with chronic hepatitis C had been exposed to GBV-C/HGV, but in almost all, the virus had been cleared; also, even chronic GBV-C/HGV infection did not affect the severity of the disease arising from HCV. Interferon alfa treatment was sometimes effective against GBV-C/HGV, and anti-E2 may be associated with clearance of GBV-C/HGV.