OBJECTIVES To compare the efficacy and safety of Entecavir and Tenofovir in nucleos(t)ide-naïve CHB patients with HBV DNA in a medical center. METHODS We included patients in WFH had used Entecavir or Tenofovir from 2011/07 to 2012/12, and excluded patients who had (1) co-infection with the HCV, HIV, TB, (2) the history of malignancy within 3 years before the first time use of ETV or TDF, (3) the history of alcohol abuse, and (4) used other anti-HBV drugs. In Statistics, we used Kaplan–Meier survival analysis to present the HBV DNA suppression and the normalization of ALT. RESULTS We identified 124 consencutive patients treated with ETV and 24 patients treated with TDF. After 18 months, the probability of complete viral suppression was 67.7% in the ETV group and 45.8% in the TDF group (P=0.49). The probability of complete ALT normalization was 87.1% in the ETV group and 83.3% in the TDF group (P=0.159). In the adverse side effects of neurologic, malaise was observed in the patients treated with ETV more than TDF (11.3% vs. 0%), but in gastrointestinal disorders, diarrhea was observed in the patients treated with TDF more than ETV (25.0% vs. 3.2%). CONCLUSIONS Entecavir and Tenofovir have no significance difference in the efficacy and safety in nucleos(t)ide-naïve CHB patients with HBV DNA greater than 6 log10 in the medical center.