Background/Aims: In this study, lamivudine-interferon (LAM/IFN) combination therapy was compared to LAM monotherapy to verify if the combination treatment might improve efficacy and reduce the emergence of LAM-resistant mutants.Methods: Fifty patients with anti-HBe-positive chronic hepatitis B were treated for 12 months with LAM at 100mg/day (26 pts) or with IFN at 5MU t.i.w.+LAM 100mg/day (24 pts). Serum ALT, HBV DNA and IgM anti-HBc were monitored during treatment and a 6-month follow-up. The polymerase gene was amplified by PCR and the region coding for YMDD motif was directly sequenced.Results: All patients normalized ALT and cleared HBV DNA during treatment. The response was maintained until the end of therapy in the LAM/IFN group, while in 5/26 initial responders treated with LAM alone, a virological and biochemical breakthrough was observed after 6-10 months, and selection for YMDD variants resulted. After therapy discontinuation, most patients relapsed; the response rate after 6 months was 17% in the LAM/IFN group and 19% in the LAM group.Conclusions: In anti-HBe-positive chronic hepatitis B, a 12-month course of LAM/IFN combination therapy is as beneficial as LAM monotherapy, however, the combination regimen appeared to prevent or delay the emergence of YMDD variants.