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Clinical resistance to tenofovir disoproxil fumarate (TDF) did not develop in any patient after 8 years of TDF treatment in a phase III clinical trial for treatment-naïve patients with chronic hepatitis B (CHB). Potent efficacy and high barrier to resistance of TDF have been established, even in patients who have been previously treated with nucleos(t)ide analogues (NUCs) or have NUCresistant hepatitis B virus (HBV) variants. We previously reported that TDF-based rescue therapy was effective in patients harboring lamivudine (LAM)-resistant or multidrug-resistant HBV variants. Moreover, two randomized controlled trials evaluating the efficacy of TDF monotherapy in patients infected with HBV variants resistant to adefovir (ADV) and entecavir (ETV) were conducted, and non-inferior antiviral efficacy compared with TDF plus ETV combination therapy was demonstrated. On the basis of in vitro and in vivo data, there was concern that HBV susceptibility to TDF may be reduced in patients with HBV strains with substitutions conferring ADV resistance (rtA181T/V and rtN236T), but TDF has shown antiviral efficacy dispelling such concern. Thus, recently updated international guidelines recommend switching to TDF or tenofovir alafenamide as the first-line treatment option for patients with HBV variants resistant to ETV. However, no long-term data have been driven from clinical practice to assess the antiviral efficacy of TDF monotherapy in patients with ETV resistance. In this issue of Clinical and Molecular Hepatology, a Korean real-world study by Jeon, et al. indicates that TDF monotherapy was as effective as TDF plus LAM or ETV combination therapy for the treatment of patients infected with HBV strains resistant to both LAM and ETV. Seventy-three patients with resistance to LAM and ETV were treated with TDF-based rescue therapy for at least 6 months. During a median TDF-based treatment period of 37 months, 63 of 73 patients (86.3%) achieved virologic response, defined as undetectable HBV DNA by quantitative polymerase chain reaction assay (<12 IU/mL). Virologic response rates in patients treated with TDF alone (n=12) were comparable to those in patients treated with TDF plus LAM (n=19) and TDF plus ETV (n=42) (88.4%, 94.7%, and 84.2%, respectively, at 24 months; P=0.200). On multivariate analysis, lower baseline HBV DNA level was an independent predictive factor of virologic response achieved by TDF-based rescue therapy (hazard ratio [HR]=0.723; See Article on Page 230 Is tenofovir monotherapy a sufficient defense line against multi-drug resistant hepatitis B virus?