Background and aims Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are effective as two first‐line anti‐viral therapies for chronic hepatitis B (CHB); however, data are limited on directly comparing the safety and effectiveness of these two antivirals. Hence, we compared the efficacy and safety of TDF and ETV on treatment‐naïve patients with CHB. Methods We performed a hospital‐based, retrospective cohort study of 257 treatment‐naïve patients with CHB receiving TDF (n = 79) or ETV (n = 178). Virological and biochemical response as well as nephrotoxicity were assessed between TDF and ETV treatment groups. Results At month 12, TDF group had faster on HBV DNA complete suppression than ETV group (p = 0.001). Multivariate analysis indicated that treatment with TDF was a significant predictor of HBV DNA suppression (HR = 1.33; 95% CI = 1.01 – 1.76; p = 0.045). In addition, HBeAg positivity (HR = 0.70; 95% CI = 0.52 – 0.96; p = 0.025) and higher baseline HBV DNA level (HR = 0.84; 95% CI = 0.76 – 0.92; p < 0.001) were significant negative predictors for viral suppression. The ALT normalization rate between these two treatment groups were similar (p = 0.114). TDF group had more populations in ≧ 20% decrease of eGFR MDRD at month 24 than ETV group (31.5% vs. 17.2%, p = 0.044), but only the baseline eGFR was the independent factor by multivariate analysis (OR = 1.05; 95% CI = 1.03 – 1.07; p < 0.001). Conclusions TDF was significantly more effective in achieving complete viral suppression beyond month 12, and there was no significance in nephrotoxicity than ETV group. Copyright © 2017, The Gastroenterological Society of Taiwan, The Digestive Endoscopy Society of Taiwan and Taiwan Association for the Study of the Liver.