Background Treatment of HBeAg-positive patients with chronic hepatitis B is not effective in most. A combination of immunomodulatory pegylated interferon alfa-2b and antiviral lamivudine might improve the rate of sustained response. Methods 307 HBeAg-positive patients with chronic hepatitis B were assigned combination therapy (100 μg/week pegylated interferon alfa-2b and 100 mg/day lamivudine) or monotherapy (100 μg/week pegylated interferon alfa-2b and placebo) for 52 weeks. During weeks 32-52 the pegylated interferon dose was 50 μg/week in both treatment groups. The analyses were based on the modified intention-to-treat population after exclusion of 24 patients from one centre withdrawn for misconduct, ten who lost HBeAg before the study start, and seven who received no study medication. All included patients were followed up for 26 weeks after treatment. Findings 49 (36%) of 136 patients assigned monotherapy and 46 (35%) of 130 assigned combination therapy had lost HBeAg at the end of follow-up (p=0.91). More of the combination-therapy than of the monotherapy group had cleared HBeAg at the end of treatment (57 [44%] vs 40 [29%]; p=0.01) but relapsed during follow-up. Patterns were similar when response was assessed by suppression of serum hepatitis B virus (HBV) DNA or change in concentrations of alanine aminotransferase. Response rates (HBeAg loss) varied by HBV genotype (p=0.01): A, 42 (47%) patients; B, ten (44%); C, 11 (28%); and D, 26 (25%). Interpretation Treatment with pegylated interferon alfa-2b is effective for HBeAg-positive chronic hepatitis B. Combination with lamivudine in the regimen used is not superior to monotherapy. HBV genotype is an important predictor of response to treatment. Background Treatment of HBeAg-positive patients with chronic hepatitis B is not effective in most. A combination of immunomodulatory pegylated interferon alfa-2b and antiviral lamivudine might improve the rate of sustained response. Methods 307 HBeAg-positive patients with chronic hepatitis B were assigned combination therapy (100 μg / week pegylated interferon alfa-2b and 100 mg / day lamivudine) or monotherapy (100 μg / week pegylated interferon alfa-2b and placebo) for 52 weeks. week in both treatment groups. The analyzes were based on the modified intention-to-treat population after exclusion of 24 patients from one center withdrawn for misconduct, ten who lost HBeAg before the study start, and seven who received no study. Patients were followed up for 26 weeks after treatment. Findings 49 (36%) of 136 patients assigned monotherapy and 46 (35%) of 130 assigned combination therapy had lost HBeAg at the e nd of follow-up (p = 0.91). More of the combination-therapy than of the monotherapy group had cleared HBeAg at the end of treatment (57 [44%] vs 40 [29%]; p = 0.01) but relapsed during follow-up. Patterns were similar when response was assessed by suppression of serum hepatitis B virus (HBV) DNA or change in concentrations of alanine aminotransferase. Response rates (HBeAg loss) varied by HBV genotype (p = 0.01): A, 42 47%) patients; B, ten (44%); C, 11 (28%); and D, 26 (25%). Interpretation Treatment with pegylated interferon alfa-2b is effective for HBeAg-positive chronic hepatitis B. Combination with lamivudine in the regimen used is not superior to monotherapy. HBV genotype is an important predictor of response to treatment.