We compared the use of prolonged synchronous combination therapy with interferon (IFN)-alpha-2b and lamivudine with the use of IFN-alpha-2b monotherapy in patients with untreated hepatitis B e antigen (HBeAg)-positive chronic hepatitis B virus (HBV) infection. Thirty-three patients received therapy with lamivudine (100 mg daily) and IFN-alpha-2b (10 million U 3 times per week) for 12 months; 16 patients received IFN-alpha-2b alone (10 million U 3 times per week for 12 months). The primary end point was sustained suppression of HBV DNA and HBeAg seroconversion, which was observed in 15 (45%) of 33 patients treated with combination therapy and in 3 (19%) of 16 patients treated with monotherapy (P=.133). Both therapeutic regimens were well tolerated. Combination therapy increased the rate of sustained suppression of HBeAg and resulted in significant improvement in Knodell histologic activity index scores, compared with monotherapy. However, there was no significant difference in rates of sustained suppression between the 2 groups at the end of follow-up.