BACKGROUND/AIMS: The efficacy of alpha-interferon (alpha-IFN) in chronic hepatitis B (CHB) is higher in patients with low serum HBV DNA or high ALT level. Lamivudine is an oral nucleoside analogue, which inhibits HBV replication. We investigated whether the alpha-IFN response is improved with simultaneous administration of lamivudine. METHODS: Previously untreated 62 CHB patients with HBeAg (+), HBV DNA (+), and elevated ALT level were randomized into 3 groups; controls (n=19), alpha-IFN monotherapy group (n=21), and combination therapy group of lamivudine and alpha-IFN (n=22). The alpha-IFN monotherapy group had 6 million units of alpha-IFN three times weekly for 24 weeks. The combination group received lamivudine 100 mg daily for 36 weeks, which was started 12 weeks before alpha-IFN administration. RESULTS: The rate of HBeAg seroconversion at 24th week after the completion of treatment was 11.8% for the control group, 23.8% for the monotherapy group, and 25.0% for the combination therapy group, showing no difference between the two therapy groups. The rates of sustained suppression of serum HBV DNA and ALT normalization in the combination therapy group were not different from those in the monotherapy group. CONCLUSIONS: The combination therapy of lamivudine and alpha-IFN does not seem to increase the rate of HBeAg seroconversion compared to alpha-IFN monotherapy in patients with CHB.