Five drugs are approved for the treatment of chronic hepatitis B: conventional interferon (IFN) alfa, lamivudine, adefovir dipivoxil, pegylated interferon (peginterferon) alfa-2a and entecavir. Conventional IFN monotherapy has a narrow range of efficacy, should be administered subcutaneously and is commonly associated with adverse effects. Lamivudine is cheaper and well tolerated, but the virological response may not be durable and prolonged lamivudine treatment is commonly associated with the emergence of drug-resistant mutants. Adefovir dipivoxil is potent but with nephrotoxicity at higher doses. Entecavir is active against both lamivudine- and adefovir dipivoxil-naïve and -resistant HBV, however, its long-term efficacy remains to be evaluated. Peginterferon alfa-2a has recently been shown to be superior to conventional IFN and lamivudine in the treatment of both HBeAg-positive and -negative chronic hepatitis B. By using peginterferon alfa-2a monotherapy, the overall virological and serological responses are around 30%-44%. However, peginterferon alfa-2a in combination with lamivudine does not improve the results at the end of follow-up. Adverse effects are usually tolerable and comparable with conventional IFN. Similar efficacy of peginterferon alfa-2b has also been demonstrated in HBeAg-positive chronic hepatitis B. These observations suggest an important and even a primary role of peginterferon alfa in the treatment of chronic HBV infection.