Conventional interferon therapy has been used for the treatment of chronic hepatitis B (CHB) for many decades. However, the use of interferon has been limited by its short half-life and high incidence of dose-related side effects. A meta-analysis investigating the short- and long-term consequences of interferon therapy showed that, whilst interferon therapy was beneficial in the short term, resulting in normalization of alanine aminotransferase (ALT) levels, loss of HBeAg, 'e' seroconversion and suppression of hepatitis B virus (HBV) DNA, the long-term benefits were less substantial. Pegylation of interferon (peginterferon alpha-2a [40 kDa]) led to improved pharmacokinetic and pharmacodynamic profiles, which translated to superior efficacy compared with conventional, nonpegylated interferon, in the treatment of chronic hepatitis C. A phase II study investigated the safety and efficacy of peginterferon alpha-2a (40 kDa) in the treatment of chronic hepatitis B. The results demonstrated a rapid and dramatic reduction in HBV DNA levels, HBeAg clearance and normalization of ALT with peginterferon alpha-2a (40 kDa) compared with conventional interferon. Furthermore, peginterferon alpha-2a (40 kDa) conferred a notably improved treatment response in patients with 'difficult-to-treat' hepatitis B infection. In conclusion, peginterferon alpha-2a (40 kDa) is a promising emerging therapy for CHB.