Unravelling the role of interferon (IFN) in the treatment of chronic hepatitis B compliance by many factors. Several mutant forms of hepatitis B virus (HBV) have recently been discovered; the most common of these is the precore mutant, characterized by hepatitis B e antigen (HBeAg) negativity and hepatitis B e antibody (HBeAb) positivity in an individual with an active HBV infection. The aim of this study was to compare the response rate to IFN therapy in patients with wild-type HBV infection and in individuals infected with the precore mutant. A second aim was to evaluate the role of an increased serum ferritin in terms of the IFN response rate in these two different types of HBV infection. IFN therapy was administered at a dose of 5 MU subcutaneously three times weekly for 6 months to 41 individuals with a chronic wild-type hepatitis B infection and 16 individuals with a precore mutant chronic HBV infection. An IFN response was defined as normalization of the serum alanine aminotransferase (ALT) level and an HBeAb to HBeAb seroconversion (in wild-type hepatitis infection), and a normalization of the serum ALT in individuals infected with a precore mutant infection. At entry, the two groups were matched for age, gender, serum ALT, serum iron, total iron binding capacity (TIBC), serum ferritin and liver histology. Forty-six per cent of the subjects with wild-type disease responded to IFN therapy. By contrast, only four of the 16 cases (25%) of the precore mutant cases responded (p < 0.05). Ferritin levels correlated well with the type of IFN response; as the serum ferritin level increased, the response rate to IFN declined. Hapatic infection caused by a precore HBV mutant is more resistant to IFN therapy than wild-type infection. The serum ferritin level appears to influence the type of IFN response achieved. Individuals with a serum ferritin level greater than 300 ng ml-1 failed to respond to IFN in 93% of the cases studied.