BACKGROUND Interferon-alfa has been used in the treatment of chronic hepatitis B for more than 20 years and has its own advantages including a definite course of therapy, no production of drug-resistant variants, and sustained efficacy. This review was to understand the role of interferon-alfa therapy in chronic hepatitis B. METHODS An English-language literature search using Medscape and MEDLINE was performed and a total of 48 articles on the treatment of chronic hepatitis with interferon-alfa or pegylated interferon-alfa were selected. RESULTS Interferon-alfa therapy was associated with a higher HBV DNA inhibition rate and HBeAg loss rate compared with controls, and it may have long-term beneficial effects in terms of HBV clearance, reduction of hepatocellular carcinoma, and prolongation of survival. Pegylated interferon-alfa was more effective than conventional interferon-alfa in the treatment of chronic hepatitis B as well as chronic hepatitis C, and was also associated with greater efficacy than conventional interferon in difficult-to-treat disease. CONCLUSIONS Interferon-alfa is still regarded as one of the first-line drugs for the treatment of chronic hepatitis B. Pegylated interferon is a more promising therapy than conventional interferon-alfa, especially in patients with refractory chronic hepatitis B.