In the past decade, many chronic hepatitis B (CHB) patients have undergone sequential treatment with lamivudine (LAM), adefovir (ADV), and entecavir (ETV) to manage antiviral resistance or insufficient suppression of HBV-DNA. Very limited data are available on the efficacy of tenofovir (TDF) rescue regimens in patients with multidrug resistance (MDR). We investigated the antiviral efficacy of TDF/LAM combination therapy versus TDF/ETV combination therapy in 52 patients who failed three previous antiviral therapies. The study subjects were treated with TDF/LAM combination therapy (n = 25) or TDF/ETV combination therapy (n = 27) for more than six months. Virologic response (VR) occurred in 39 (75%) patients (19 patients belonged to the TDF/LAM group and 20 patients belonged to the TDF/ETV group). The VR rates were not different between the TDF/LAM and TDF/ETV groups (56.0% vs 51.9% at month 12, and 72.0% vs 78.8% at month 18; log rank P = 0.515). In addition, treatment efficacy of TDF/LAM combination or TDF/ETV combination was not statistically different according to types of MDR. In multivariate analysis, absolute HBV-DNA level at the start of TDF rescue treatment (P < 0.001; OR, 0.452; 95% CI, 0.306-0.666) was only significantly associated with VR. TDF/ETV combination therapy was not associated with higher rate of VR compared with TDF/LAM combination therapy in MDR CHB patients. These results raise the suspicion about the superiority of the combination therapy over TDF monotherapy. The lower HBV-DNA levels at the start of TDF-based rescue therapy were associated with higher VR.