Summary Patients with chronic hepatitis B and active viral replication had no change in DNA-polymerase (DNA-p) and HBeAg when treated with weekly injections of lymphoblastoid alpha-interferon (IFN) for 4–10 weeks. Daily IFN (2.5 MU/m 2 for a period of 4 weeks) was associated with a significant fall ( P < 0.05) in DNA-p but not in HBeAg; DNA-p remained or became negative in 3 out of 10 patients after stopping therapy. Combination of IFN and intravenous acyclovir (ACV, 15 mg/kg twice daily) led to a significantly greater fall in DNA-p and HBeAg, while tolerance of the combination therapy was excellent. Four out of 5 patients became DNA-p-negative and three HBeAg-negative; subsequently two became HBsAg-negative with anti-HBs. We conclude that weekly IFN appears ineffective. Daily IFN depressed hepatitis B virus replication, but does not change markedly the natural course of the disease. Combination therapy with ACV may be more effective than IFN alone and is well tolerated.