The standard treatment of an HBeAg-positive, HBV-DNA-positive chronic hepatitis B patient is a 16-week course of 10 MU alpha-interferon thrice weekly. However, the overall therapeutic effect, as measured by disappearance of the HBe-antigen, is estimated at 30%. Improvement is possible by better selection of the patient, modifications in the treatment schedule, or combination therapy. In the selection of possible candidates for combination therapy, the second generation nucleoside analogues with activity against hepatitis B are good candidates. In clinical studies, lamivudine and famciclovir are used, both of which can reduce serum HBV-DNA to levels below 1 pg/ml within weeks. The ongoing clinical studies address the efficacy and safety of these drugs after prolonged exposure, in combination with alpha-interferon and around liver transplantation in patients with decompensated liver disease.