The primary goal of treatment in hepatitis B e antigen (HBeAg)-negative patients with chronic hepatitis B (CHB) is potent and durable suppression of hepatitis B virus (HBV) replication. It results in biochemical and histological remission of CHB and is the prerequisite for the prevention of cirrhosis, its life-threatening complications and hepatocellular carcinoma. Responses that are durable after the cessation of treatment are referred to as sustained virological responses, whereas those persisting under therapy are referred to as treatment-maintained virological responses. Treatment paradigms of sustained virological response in HBeAg-negative CHB are practically restricted to conventional IFN-alpha and pegylated interferons (peg-IFNs), and are limited only to patients with compensated liver disease. Long-lasting maintained virological responses without HBV resistance in HBeAg-negative CHB are achievable by all approved nucleos(t)ide analogues (lamivudine, adefovir and entecavir) in highly variable rates, depending on their potency, rapidity of virological response and genetic barrier to resistance. The maintenance of response under 5 years of adefovir treatment represents the most effective treatment paradigm for HBeAg-negative CHB, whereas such long-term data with entecavir and tenofovir monotherapy may become available in the near future. In patients with lamivudine-resistant HBV mutants, the recommended treatment strategy is to add adefovir at the same time as continuing treatment with lamivudine. There are no treatment paradigms as yet of combination therapy from the very outset with two nucleoside analogues for use in treatment-naive patients.