Of the hepatitis B e antigen-negative chronic hepatitis B patients with more than 1 year of sustained hepatitis B virus (HBV) suppression during therapy, the 1-year clinical relapse rate after cessation of entecavir therapy was 45%, of which 25.6% occurred within 6 months. The events after cessation of another preferred drug tenofovir were investigated. A retrospective-prospective study was conducted in 85 hepatitis B e antigen-negative chronic hepatitis B patients with sustained HBV suppression who had stopped tenofovir therapy and were monitored every 1 to 3 months for a median duration of 39 weeks (range, 4-133 wk). Clinical relapse occurred in 38 patients, 57.9% and 86.8% within 3 and 6 months, respectively, with an estimated 1-year cumulative incidence of 52%. The optimal duration of therapy and consolidation therapy were calculated to be 3 and 2 years, respectively. Of the relapsers, 81.6% and 57.9% showed an alanine aminotransferase level greater than 5 and 10 times the upper limit of normal, respectively, 23.7% showed a bilirubin level of 2 mg/dL or greater, and 2 developed hepatic decompensation. Relapsers had significantly higher pretherapy baseline hepatitis B surface antigen level, more prior anti-HBV therapy experience, later alanine aminotransferase level normalization, and a shorter duration of treatment and consolidation therapy. Cox regression analyses showed that treatment for more than 3 years combined with consolidation therapy for more than 2 years was an independent significant manageable factor of clinical relapse (adjusted hazard ratio, 0.387; P= .008). With this combination, the clinical relapse rate was reduced to 30%. Clinical relapses occurred mostly within 6 months, with high alanine aminotransferase and serum bilirubin levels. Closer monitoring, monthly in the first 3 to 6 months, with timely re-treatment is mandatory for a safe cessation of tenofovir therapy.