Objective: To systematically review the effectiveness of pegylated interferon (PEG), lamivudine (LAM), adefovir (ADF) and entecavir (ENT) in treating CHB. Methods: Pubmed, Embase, Cochrane, and Econlit were searched for randomized controlled trials assessing the efficacy of the selected drugs for treating CHB published in the English language from dates of inception to January 2007. Patients were considered to have CHB if they had elevated ALT levels and active viral replication. Monotherapy, combination and sequential therapies were included. Among trials that met our inclusion criteria, we abstracted data describing normalization of ALT, HBV DNA, sustained biochemical response, HBeAg seroconversion, histological improvement, drop-outs and adverse events. Intention-to-treat data were combined using a random-effects meta-analysis, with missing data considered as treatment failures. Outcomes were expressed as relative risks with 95% confidence intervals. Results: The initial search yielded 2064 references, 127 were excluded due to inadequate blinding, allocation concealment, randomization and reporting of outcomes; 20 studies were included. Trials involved 5573 patients (4121 males, 1309 females), ranging in size from 200-814 patients. Mean age was 40.7. Eleven trials studied HBeAg-positive patients, four trials studied HBeAg-negative patients, and four trials studied both. Due to small numbers of trials for comparison led to pooling of HBeAg-positive and HBeAg-negative studies. No treatment was superior for all outcome measures. Monotherapy was superior to placebo. Comparisons of single drugs favored treatment with ADF or ENT over LAM or PEG. LAM was superior to PEG with better clinical outcomes and fewer adverse events and patient dropouts. Combination and sequential treatments were not superior, however comparisons were limited by our one-year follow-up. Conclusion: Monotherapy with ADF or ENT are the most attractive treatment options within the first year of treatment. Further research on combination and sequential therapies may provide better options but presently insufficient evidence exists to support this approach.