Serum HBeAg‐negative chronic hepatitis B, which is usually a late stage of chronic hepatitis B virus infection, is difficult to treat, because it is characterized by fluctuating alanine transaminase values resulting in hepatitis flares, accelerated progression to cirrhosis and liver cancer. Antiviral treatment, either long‐term nucleot(s)ide therapy or 1‐year administration of pegylated interferon (PEG‐IFN), is therefore necessary to limit the course of the disease. A sustained virological response to PEG‐IFN is achieved in approximately 1/4 of the patients, with significant rates of HBsAg seroclearance. While waiting for the results of several studies whose goal is to improve the long‐term efficacy of PEG‐IFN, the treatment strategy can be optimized by a careful selection of patients, discontinuation of PEG‐IFN as early as possible in primary non‐responders and extended therapy (up to 96 weeks) in responders.