Although LAM, ADV, and LdT are approved for the treatment of chronic HBV infection, high rate of resistance has plagued therapeutic use. At present, the two first line nucleoside/ nucleotides are ETV and TDF. ETV is a potent antiviral that effectively suppresses HBV DNA replication. It has a high genetic barrier for resistance in Atractylenolide-III HBeAg-positive and HBeAg-negative patientswith a cumulative resistance probability of 1.2% after 5 years of treatment. However, in lamivudine-refractory patients, the cumulative probability of genotypic ETV resistance developing over 5 years is 51%. TDF is newer and considered a higher efficiency antiviral drug with a high genetic barrier. To date, no evidence exists to show development of resistance to TDF up to 144 weeks of therapy. Moreover, TDF has been demonstrated to be effective in patients with both adefovir and lamivudine failure. TDF is more effective than ETV to achieve rapid viral suppression in HBeAg-positive chronic HBV patients. Additionally, the Bayesian meta-analysis by Woo et al. highlighted TDF as the more effective agent for HBeAgnegative patients during the first year of therapeutic intervention. TDF is proposed to be superior to ETV for treating chronic HBV; however, a more promising result was shown by multiple studies claiming that both are similar in both efficacy and safety. Due to the small sample sizes of past studies and subsequent limited data for comparing the two drugs, a more definitive conclusion is lacking. Herein, we conducted this metaanalysis by integrating published drug-based data to compare efficacy and safety of TDF and ETV and Kaempferide ultimately provide evidence for clinical decisions. To achieve long-term antiviral success, a high barrier to resistance is also critical for antiviral agents. TDF and ETV both present low rates of resistance and have had success in patients failing to previous NA therapy. Although resistance to ETV requires three mutations, pre-existing LAM resistance-associated mutations provide some foundation for ETV resistancesince resistance to ETV shares two common mutationswith LAM. In patients with LAM-resistant HBV, a high 6-year resistance rate of 57% has been suggested for ETV. Undetectable HBV DNA is not always achieved and virological breakthrough has occurred with ETV. Additionally, it has been reported that sequential monotherapy of ETV can further promote multidrug resistant mutations. Therefore, ETV monotherapy no longer be considered an optimal first-line therapy against LAM-resistant HBV. Moreover, TDF is a beneficial alternative for LAM failure patients, despite an incomplete resistance profile. Some limitations merit consideration. In our study, major included studies were non-RCTs. It has been reported that some factors, geographic, ethnic or disease status differences are possibly associated with agent efficacy. However, considering limited studies numbers for each factor, further analysis was restricted. Besides, due to the limited number of studies, analysis for some effect indicators might be underpowered. Although current related studies have shown TDF may be used as an alternative agent against HBV infection in drug safety and resistance, this study results still need more studies and reasonable statistic methods used to explore safety and tolerability of these drugs. Our meta-analysis indicates that ETV and TDF are comparable in efficacy and safety to sustain HBV DNA suppression with limited side effects.