The aim of chronic hepatitis B (CHB) antiviral therapy is to persistently suppress HBV and improve survival by preventing the progression of liver damage to cirrhosis, end-stage liver disease or hepatocellular carcinoma (HCC), thus preventing early liver-related death. In HBeAg-negative patients who do not or will not respond to or be treated with pegylated interferon (PEG-IFN), the administration of third generation nucleot(s)ide analogues (NAs), i.e. entecavir (ETV) and tenofovir disoproxil fumarate (TDF), is the treatment of choice. Long-term administration of ETV or TDF suppresses HBV replication in >95% of patients after 5 years of treatment with high rates of biochemical normalization, regression of fibrosis and cirrhosis at histology as well as preventing clinical decompensation but not HCC, in compensated cirrhosis and improving survival. No major safety issues have been recorded with either drug. The need for long-term, perhaps indefinite, treatment is the main limitation of NA therapy with possible associated costs, unknown long-term safety and the low rates of HBsAg seroclearance. The latter is important since HBsAg seroclearance is still the best stopping rule for HBeAg-negative NA-treated patients, including those with cirrhosis. For this reason new trials based upon a combination of PEG-IFN and third generation NAs in both naïve and NA-responder HBeAg-negative patients are ongoing.