A randomized controlled trial of recombinant interferon alfa-2b has been initiated in patients with chronic active hepatitis who were negative for serum hepatitis B e antigen but positive for serum hepatitis B virus DNA and hepatitis B core antigen expression in the liver. Twenty-five patients received interferon alfa-2b 3 million units thrice weekly for 14-16 weeks and 25 served as untreated controls. Seventeen patients in the treatment and 18 in the control group have already completed a 12-month period of observation. Interferon alfa-2b was well tolerated by all patients. At the end of therapy, complete responses, defined as disappearance of hepatitis B virus DNA from serum and return of alanine aminotransferase to normal, were observed in 10 (59%) of the 17 treated patients compared to none in the control group (p less than 0.01). Twelve months after the onset of interferon alfa-2b therapy, 11 (65%) of the 17 treated patients were complete responders compared to 2 (11%) of 18 in the control group (p less than 0.01). Fifty per cent (4/8) of complete responders to interferon alfa-2b therapy, followed for 16-24 months, experienced reactivations of hepatitis B virus replication with reappearance of serum hepatitis B virus DNA and a return of serum alanine aminotransferase activity. The response to interferon alfa-2b therapy appeared to be independent of pre-treatment serum alanine aminotransferase and hepatitis B virus DNA levels.