BACKGROUND & AIMS: Information regarding long-term HBsAg kinetics during treatment with nucleoside/nucleotide analogues is limited. The aim of the present study was to assess whether finite nucleoside/nucleotide analogue treatment duration could be envisaged during the patient's lifetime. METHODS: Patients with chronic hepatitis B receiving different schedules of nucleoside/nucleotide analogues were followed for a median duration of 102months, i.e., 8.5years (interquartile range: 88-119months). Long-term HBV DNA and HBsAg level kinetics were modeled in order to estimate time to clear HBsAg during therapy in patients with undetectable HBV DNA. RESULTS: Antiviral therapy was associated with a slow but consistent reduction in the level of HBsAg in most of the patients. Three patterns of HBsAg level declines were identified: decline during both the detectable and undetectable HBV DNA phases; decline during the HBV DNA detectable period only; decline during the HBV DNA undetectable period only. The mean HBsAg titer at the time when HBV DNA became undetectable was 3.29±0.49Log10international units (IU)/ml, and the mean slope was -0.007±0.007Log10IU/month, i.e., an average decline of 0.084Log10IU/year. The corresponding calculated median number of years needed to clear HBsAg was 52.2years (interquartile range: 30.8-142.7). CONCLUSIONS: This study, based on the very long-term follow-up of patients with chronic hepatitis B treated with potent nucleoside/nucleotide analogues, shows that HBsAg clearance is unlikely to occur during the patient's lifetime, even if HBV replication is well controlled. Thus, lifetime therapy is required in the vast majority of HBV-infected patients.