The aim of our study was to assess the efficacy and tolerability of lamivudine alone versus lamivudine plus alpha-interferon for treatment of chronic active hepatitis B, anti-HBe positive. In all, 59 patients were randomly divided into 3 groups: A) 21 patients received lamivudine at 100 mg/daily orally for 52 weeks; B) 20 patients received lamivudine at 100 mg/die plus alpha-interferon at 6 MU subcutaneously three times weekly for 52 weeks; C) 18 patients received the same combination therapy for 40 weeks after pre-treatment with lamivudine for 12 weeks. The complete sustained response in the three groups was 33.3% vs 35.0% vs 33.3%, respectively. Our study demonstrates that in anti-HBe positive chronic hepatitis B a 12-month course of lamivudine plus a-interferon combination therapy is as beneficial as lamivudine monotherapy. Moreover, the combination therapy for 40 weeks after pre-treatment with lamivudine for 12 weeks did not increase the sustained response.