We compared rates of relapse of hepatitis B virus (HBV) infection between patients with HBV genotype B vs genotype C infection after cessation of entecavir or tenofovir disoproxil fumarate (TDF) therapy. All patients included in the study were HB e antigen (HBeAg)-negative.We performed a retrospective study of 460 HBeAg-negative patients without cirrhosis in Taiwan who had stopped entecavir or TDF treatment for at least 12 months; data were collected from 2007 through 2015. All patients fulfilled the stopping criteria proposed by the APASL 2012 guidelines. Patients were evaluated every 1-3 months during the first 6 months after stopping therapy and then every 3 months until their last hospital visit; HB surface antigen (HBsAg) was measured in serum samples collected before treatment, after 12 months of treatment, and at the end of treatment. Virologic relapse was defined as a serum level of HBV DNA >2000 IU/mL after the cessation of treatment; clinical relapse was defined as increase in alanine aminotransferase more than 2-fold the upper limit of normal (40 U/L) and level of HBV DNA >2000 IU/mL after stopping treatment.Significantly higher proportions of patients with HBV genotype B infection had virologic and clinical relapse and retreatment than patients with HBV genotype C infection, among all patients and among patients matched by propensity sore. Patients who discontinued TDF therapy had significantly higher rates and earlier times of virologic and clinical relapse than patients who discontinued entecavir therapy, among all patients and propensity score-matched patients. Multivariate analysis showed that TDF therapy, old age, HBV genotype B, and higher end of treatment HBsAg level were independently associated with virologic and clinical relapse. Five-year rates of virologic and clinical relapse were low (19.2% and 15.4%, respectively) in patients with a combination of end of treatment level of HBsAg of 100 IU/mL or less and HBV genotype C infection. Rates of off-therapy HBsAg loss, development of hepatocellular carcinoma, and hepatic decompensation did not differ significantly between patients with HBV genotypes B vs C infection or between the entecavir vs TDF groups.Higher proportions of HBeAg-negative patients with HBV genotype B infection have virologic and clinical relapse and retreatment than patients with HBV genotype C infection, after cessation of entecavir or TDF therapy.