It is well-known that consistently high hepatitis B virus (HBV) DNA levels increase the risk of fibrosis progression and hepatocellular carcinoma (HCC) development in patients with chronic hepatitis B (CHB) [1,2]. Therefore, the primary goal of CHB treatment is complete suppression of HBV DNA by antiviral treatment [3]. Before the introduction of nucleos(t)ide analogues (NAs) with a high genetic barrier, such as entecavir (ETV) and tenofovir disoproxil fumarate (TDF), long-term treatment of NAs with a low genetic barrier, such as lamivudine (LAM), adefovir dipivoxil (ADV) and telbivudine (LdT), led to drug resistance in many CHB patients [3-5]. Until the introduction of ETV or TDF, the standard treatment was to add ADV to LAM or LdT for the treatment of CHB patients with LAM or LdT resistance [6]. However, CHB patients receiving LAM or LdT/ADV combination therapy often show a suboptimal response [7]. In patients with this suboptimal response, it is known that the risk of developing resistance to various NAs increases, as well as the risk of developing end-stage liver disease and HCC [8]. Therefore, the current guidelines recommended that HBV DNA maintain serum HBV DNA level below the detection limit of real-time polymerase chain reaction as the primary treatment goal [3,5,9]. In the past, a combination of ETV-based regimens had been attempted to treat the CHB patients who had suboptimal response to LAM or LdT/ADV combination therapy [10,11]. However, since the introduction of TDF with strong antiviral efficacy in the treatment of CHB, TDF monotherapy or TDF+other NAs regimens have been attempted to treat patients with various drug resistance [12-16]. Berg et al. [12] conducted a prospective randomized controlled trial to compare the antiviral effects of TDF monotherapy and TDF+emtricitabine (FTC) combination therapy in patients with suboptimal responses to ADV. According to the results of their study, complete virologic response (CVR) of TDF monotherapy and TDF+FTC combination therapy groups was 81% and 81%, respectively, at 48 weeks; and there was no difference between the two groups [12]. In a retrospective study of CHB patients with suboptimal response to ADV with or without NAs in LAM-resistant CHB, Cho et al. [13] showed that the CVR of TDF monotherapy group and TDF with NA combination group at 48 weeks was 81.8% and 85.9%, respectively; and there was also no significant difference between the two groups (P =0.075). In a small randomized controlled trial, Lee et al. [14] compared the antiviral efficacy between switching to TDF+NAs therapy and continuing current ADV+NA therapy in patients with suboptimal response to ADV-based therapy. The results of their study showed that TDF+NAs therapy was significantly higher in CVR compared to continued ADV+NA (87.5% vs. 37.5% at 48 weeks, P =0.002) [14]. In addition, TDF showed good effects on CHB patients with ETV, ADV resistance, and multidrug resistance, as well as LAM resistance [15,16]. Lim et al. [15] compared the effects of TDF monotherapy versus TDF and ETV combination therapy in patients with ETV-resistant CHB with multiple drug failure in a randomized controlled trial, and the CVR of TDF and TDF+ETV groups was 71% and 73%, respectively, at 48 weeks. There was no difference between the two groups (P =0.99) [15]. In a study comparing the effects of TDF monotherapy versus TDF and ETV combination therapy in ADV-resistant CHB patients with multiple drug failure, the CVR at 48 weeks was 62% and 63.5% for TDF and TDF/ETV groups, respectively; and there was also no significant difference between the two groups (P =0.88) [16]. Moreover, the results of several different studies showed no difference in CVR between TDF monotherapy and TDF+ETV combination therapy, the combination regimen of the most potent NAs to date, in CHB patients who are resistant to various NAs (Table 1).