OBJECTIVES: Assess comparative efficacy of combination therapy of interferon-alpha with lamivudine versus lamivudine monotherapy for HBeAg-positive chronic hepatitis B (CHB). METHODS: Searched MEDLINE, SCI-Expand, Current Content Connect, Cochrane Library and Chinese Biomedical Database to April 25, 2006, and screened reference lists of eligible trials. Randomized trials were included if comparing lamivudine plus interferon-alpha with lamivudine alone in patients with HBeAg-positive and ALT-elevated CHB. We recorded interventional and patient characteristics. Quality of trials was assessed by six items based on the Cochrane recommendation. We used fixed and random effect model meta-analysis to pool the data. Two types of interventional strategies were available: a) lamivudine in both arms were administrated 52 weeks; and b) lamivudine was administrated 24 weeks in combination arm while 52 weeks in monotherapy. We stratified trials for analysis, and performed sensitivity analysis based on the dose of interferon-alpha, where appropriate. RESULTS: Twenty randomized trials were included. Quality was moderate in most. Both at 24-week (for both types) and 52-week (for type b) of treatment, loss of HBeAg (RR = 2.54 and 1.62, 95%CI = 1.91-3.37; 1.13 - 2.33, p = 0.000 and 0.009) and HBeAg seroconversion (RR = 3.12 and 1.73, 95%CI = 2.07 - 4.70; 1.20 - 2.51, p = 0.000 and 0.004) were significantly higher in combination than lamivudine monotherapy. Loss of HBV DNA, loss of HBsAg and normalization of ALT were not statistically significant. Two strategy types were limited in follow-up data. However, loss of HBV DNA was significantly higher in combination group after a 26-week follow-up in both strategies; no significant difference was found in serological and biomedical markers. CONCLUSION: It was suggested that combination therapy might be superior to lamivudine therapy in clearing serological markers but not for virological and biomedical ones during treatment. Further study was needed to investigate the long-term benefit of combination therapy.