ABSTRACT— Twelve hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), hepatitis B virus DNA polymerase (HBV-DNAp) and hepatitis B virus DNA (HBV-DNA) positive patients with chronic active hepatitis (CAH) were treated with doses of either 20 times 106 IU/m2 or 10 times 106 IU/m2 body surface of recombinant interferon (rIFN)-alpha-2A, I.M., twice a week, during a period of 6 months. No appreciable differences with respect to clinical history, liver function tests and markers of HBV replication between the two groups were apparent at the time of entry into the trial. At the third month of treatment HBV-DNAp became negative in 10 out of 12 patients (83%). After a 15-month follow-up, HBV-DNAp, HBV-DNA and HBeAg were negative in 7 out of 12 patients (38%) (responders). Furthermore, at 24 months, 2 non-responder patients became HBV-DNA and HBV-DNAp negative and one responder lost serum HBsAg. In addition, HBsAg concentration, GPT level and histological Knodell's index decreased significantly in the responder patients, while no changes were observed in non-responders. Five out of six patients who received a low rIFN dose responded to the treatment, and only 2 out of 6 with a higher dose. No unacceptable toxicity was noted in any of the 12 patients. All of them completed the course of treatment. The results suggest that long-term rIFN-alpha-2A therapy has an antiviral effect in CAH due to HBV infection and is well tolerated.