The clinical significance of GB virus C (GBV-C E2) antibody is under investigation. The prevalence rates of GBV-C RNA and antibody to GBV-C E2 glycoprotein were determined in a population of 123 Egyptian anti-hepatitis C virus (HCV)-positive patients with chronic liver disease (CLD) who had not been treated previously with interferon. Sera were tested for GBV-C RNA by the LCx assay (Abbott Laboratories, North Chicago, IL), and for GBV-C E2 antibody by enzyme immunoassay. GBV-C RNA was present in 11.4% of patients. GBV-C E2 antibody was detected in 55.9% of GBV-C RNA-negative patients and in 2.2% of GBV-C RNA-positive patients (P = 0.006). GBV-C RNA was associated significantly with a history of schistosomiasis (relative risk [RR] = 5.83, 95% confidence interval [CI] 1.99-17.14, P < 0.005) but not with parenteral risk factors. The presence of GBV-C E2 antibody was not associated with age, gender, parenteral risk factors, schistosomal infection, or HCV viremia. The HCV genotype and level of viremia were similar in GBV-C anti-E2-positive and negative patients. There was a trend toward more severe histological disease with anti-E2 seropositivity (RR = 1.45, 95% CI 0.89-2.45, P = 0.11), an association which was independent of the evidence of schistosomiasis. It is concluded that GBV-C infection is common among HCV-infected Egyptian patients with CLD due to HCV infection. A significant negative correlation between the GBV-C viremia and GBV-C E2 antibody suggests that an antibody response is associated with viral clearance. This antibody response presumably occurs spontaneously, as none of the patients had received antiviral therapy. The unexpected association between GBV-C RNA and schistosomiasis suggests that nonparenteral or occult parenteral routes of GBV-C infection are likely to be important.