BACKGROUND & AIMS: Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are potent antiviral agents that might have additive or synergistic antiviral activity in treatment of patients with chronic hepatitis B (CHB). We compared the efficacy and safety of ETV monotherapy with those of a combination of ETV and TDF. METHODS: We performed a randomized, open-label, multicenter, superiority study of 379 nucleos(t)ide-naïve patients with hepatitis B e antigen (HBeAg)-positive (n = 264) or HBeAg-negative (n = 115) CHB. Subjects were given ETV 0.5 mg (n = 182) or a combination of ETV 0.5 mg and TDF 300 mg (n = 197) for 100 weeks. RESULTS: At week 96, comparable proportions of patients in each study arm achieved the primary end point of a level of hepatitis B virus (HBV) DNA <50 IU/mL (83.2% vs 76.4%; P = .088). Among HBeAg-positive patients, a greater proportion given combination therapy achieved levels of HBV DNA <50 IU/mL than those given ETV alone (80.4% vs 69.8%; P = .046). However, this difference was observed only in patients with baseline levels of HBV DNA ≥ 10(8) IU/mL (79% vs 62%) and not in those with baseline levels of HBV DNA <10(8) IU/mL (83% in both arms). Rates of HBeAg loss and HBeAg seroconversion were comparable between groups, whereas the rate of alanine aminotransferase normalization was greater in the ETV monotherapy group. No HBV variants associated with ETV or TDF resistance were detected. Safety profiles were consistent with previous reports of ETV or TDF monotherapy. CONCLUSIONS: The antiviral efficacy of ETV monotherapy is comparable to that of ETV plus TDF in a mixed population of nucleos(t)ide-naïve patients with CHB (70% HBeAg positive). The combination therapy could provide an incremental benefit to HBeAg-positive patients with baseline levels of HBV DNA ≥ 10(8) IU/mL.