Lamivudine and famciclovir combination therapy has been used in patients with chronic HBeAg-positive hepatitis B to enhance the antiviral effect and reduce the risk of development of resistance. Interferon-alpha (IFN-alpha) can theoretically be added to the regimen to further improve the antiviral effect. Twenty patients with HBeAg-positive chronic hepatitis B were given lamivudine and famciclovir combination therapy for 24 weeks. After 12 weeks of treatment, patients were randomized on a 1:1 basis to either the addition of IFN-alpha 2b or no addition for the last 3 months of therapy. The decline in HBV DNA levels, the loss of HBeAg and the HBeAg seroconversion rate were assessed. Patients with loss of HBeAg and/or development of anti-HBe were followed up for at least 1 y after stopping treatment. Four of 19 patients (21%) had lost HBeAg and/or developed anti-HBe 24 weeks after stopping treatment, 1 of whom had received additional IFN-alpha. During long-term follow-up post-treatment, 2/19 patients (10.5%) had a durable HBeAg seroconversion. The mean HBV DNA level declined by 5 logs during the first 12 weeks of treatment. Addition of IFN-alpha during the last 3 months of treatment did not result in any further decline in HBV DNA levels compared with the non-IFN-alpha-treated group, nor in any increase in the HBeAg seroconversion rate. In conclusion, lamivudine and famciclovir combination treatment induced seroconversion from HBeAg to anti-HBe in 4/19 patients, 2 of whom became long-term responders. Addition of IFN-alpha did not improve the seroconversion rate.