Aims: Currently, for patients with lamivudine (LAM)-resistant CHB infection,switching to or adding on tenofovir (TDF) are consideredas therapeutic options. Little data are available on the comparisonof long-term efficacy of TDF-based rescue therapy and LAM/adefovir(ADV) combination therapy in patients with LAM-resistant chronichepatitis B infection.Methods: One hundred ninety-seven patients received LAM plus ADV,and 53 patients received TDF-based rescue therapy. Patients whoreceived TDF-based rescue therapy were treated with TDF alone (n= 30) or TDF/LAM combination (n = 23). A matched study populationwas constructed to compare the antiviral efficacy of TDF-based rescuetherapy and LAM/ADV combination therapy by a propensity scoreanalysis.Results: Eighty-eight patients from the LAM/ADV therapy group and 44 patients from the TDF based rescue therapy group were selectedafter matching propensity score with 2:1 ratio. Virologic response(VR) was observed in 97.7% (43/44) of patients in the TDF groupand in 79.5% (70/88) of the patients in the LAM/ADV group. Therate of VR in the TDF group was higher than that of the LAM/ADVgroup (P = 0.004). To determine the impact of baseline viral loadon the response to treatment, a post hoc exploratory analysis wasperformed. Among the patients with baseline HBV DNA level > 104IU/mL, a higher proportion of patients in the TDF group than in theLAM/ADV group achieved VR (95.5 vs. 65.9%, P < 0.001). In contrast,among patients with baseline HBV DNA level < 104 IU/mL, VR rateswere not different between the LAM/ADV and TDF groups (73.0vs. 99.5% at month 12, and 93.2 vs. 100% at month 24; log rankP = 0.885). No major clinical side effects were reported during thetreatment with either TDF or LAM/ADV groups.Conclusions: long-term efficacy of TDF-based rescue therapy wouldbe more superior to the LAM/ADV combination therapy, in the managementof LAM- resistant patients. However, in the patients withbaseline HBV DNA level <104 IU/mL, LAM/ADV combination therapywas as effective as TDF-based rescue therapy in maintaining the viralsuppression.