A substantial number of patients with chronic hepatitis C does not respond to treatment with interferon and ribavirin, the approved drugs to treat this viral infection. In vitro studies have shown that morphine, which exerts its effects by binding to opioid receptors, enhances the expression of hepatitis C RNA in hepatitis C-replicon containing liver cells, and that it interferes with the antiviral effect of interferon on the hepatitis C virus. Met-enkephalin, one of the endogenous opioid peptides, can bind to the same receptors to which morphine binds, triggering similar receptor-mediated effects. The liver in cholestasis can express Met-enkephalin immunoreactivity (MEIR). MEIR can also be detected in the liver of some patients with chronic hepatitis C. This finding suggests that Met-enkephalin is produced by or that it accumulates in the liver of patients with this viral hepatitis. Analogous to the effect of morphine on the hepatitis C-replicon containing liver cells, we hypothesize that Met-enkephalin enhances the replication of the hepatitis C virus in liver cells, and that it interferes with the antiviral effect of interferon, contributing to the lack of efficacy of this medication in the treatment of this viral infection in some patients. If this hypothesis is correct, the study of opiate antagonists in combination with antiviral therapy in patients with hepatitis C expressing MEIR in their livers merits consideration.