AbstractResponse to ribavirin therapy (1,000‐1,200 mg/day for 6 months) was evaluated in nine patients with chronic hepatitis C virus (HCV) infections who had previously failed to respond to a 6‐month course of alpha‐interferon. All had chronic active hepatitis with elevated serum aminotransferase activities (mean ± SD = 138 ± 66IU/I). During ribavirin therapy, three showed a complete response (normalized serum ami‐notransferase), although in one patient this returned to the pretreatment level 2 months after treatment was stopped. Three others showed a partial response (serum aminotransferase reduction by ⩾50;%) and the remainder showed no response. There were no consistent changes in HCV‐RNA (positive strand) in serum, liver, or peripheral blood mononuclear cells during therapy, but two patients lost HCV‐RNA from serum and three of five patients with negative strand HCV‐RNA in their livers lost this putative replicative form of the virus. The findings suggest that ribavirin may exert its effects by suppressing viral replication rather than by eradicating the virus, at least in this group of patients, and that the drug may have some benefit in selected cases of chronic hepatitis C that are resistant to inter‐feron. However, peripheral blood mononuclear cells represent a major extrahepatic reservoir of HCV and the present regimen of ribavirin therapy did not significantly affect this situation. More prolonged therapy may be required to eradicate the virus from this large pool of cells with the potential to continually reinfect the liver. ©