Twenty-one adult patients with chronic hepatitis B and active viral replication as indicated by positivity for hepatitis B e antigen and hepatitis B virus DNA, with increased DNA polymerase levels for more than 6 months, were entered into a prospective trial of low-dose recombinant human alpha-interferon therapy. All patients were treated with 5 million units of recombinant interferon alfa-2b given subcutaneously every other day for 12 weeks. During treatment, 18 patients (86%) showed a significant reduction of DNA polymerase levels (p less than or equal to 0.001), which reached normal values in ten (48%). After 10 months' mean follow up, seven patients (33%) were hepatitis B e antigen negative and five (24%) subsequently became positive for antibodies to e antigen. By 27 months, nine patients (43%) were both hepatitis B e antigen negative and e antibody positive. Only one patient became permanently negative for hepatitis B surface antigen. One patient relapsed during the second year of follow up. Side effects necessitated withdrawal of therapy in two patients: one due to worsening thrombocytopenia after two doses of interferon (data omitted from the study results) and one due to a local reaction at the injection sites. Our data indicate that small doses of recombinant interferon alfa-2b given during a 12-week period induce a significant reduction in viral replication and approximately triple the spontaneous seroconversion rate observed in patients with chronic hepatitis B.