Background Multidrug-resistant HBV continues to be an important clinical problem. The TDF-109 study demonstrated that TDF± LAM is an effective salvage therapy through 96 weeks for LAM-resistant patients who previously failed ADV add-on or switch therapy. We evaluated the 5-year efficacy and safety outcomes in patients receiving long-term TDF± LAM in the TDF-109 study. Methods A total of 59 patients completed the first phase of the TDF-109 study and 54/59 were rolled over into a long-term prospective open-label study of TDF± LAM 300 mg daily. Results Results are reported at the end of year 5 of treatment. At year 5, 75% (45/59) had achieved viral suppression by intent-to-treat analysis. Per-protocol assessment revealed 83% (45/54) were HBV DNA undetectable. Nine patients remained HBV DNA detectable, however 8/9 had very low HBV DNA levels (<264 IU/mL) and did not meet virological criteria for virological breakthrough ( VBT). One patient experienced VBT, but this was in the setting of documented non-compliance. The response was independent of baseline LAM therapy or mutations conferring ADV resistance. Four patients discontinued TDF, one patient was lost to follow-up and one died from hepatocellular carcinoma. Conclusions Long-term TDF treatment appears to be safe and effective in patients with prior failure of LAM and a suboptimal response to ADV therapy. These findings confirm that TDF has a high genetic barrier to resistance is active against multidrug-resistant HBV, and should be the preferred oral anti- HBV agent in CHB patients who fail treatment with LAM and ADV. [ABSTRACT FROM AUTHOR]