Background & Aims: Long-term treatment with tenofovir disoproxil fumarate (TDF) alone, or in combination with emtricitabine (FTC) is associated with sustained viral suppression in patients with lamivudine resistant (LAM-R) chronic hepatitis B (CHB). Methods: LAM-R CHB patients were randomised 1:1 to receive TDF 300 mg or FTC 200 mg and TDF 300 mg once daily in a prospective, double blind, study. The proportion of patients with plasma hepatitis B virus (HBV) DNA <69 IU/m1 (<400 copies/ml) at week 96 (primary efficacy endpoint) was reported previously. Here we present week 240 follow-up data. Results: Overall, 280 patients were randomised to receive TDF (n = 141) or FTC/TDF (n = 139), and 85.4% completed 240 weeks of treatment. At week 240, 83.0% of patients in the TDF arm, and 82.7% of patients in the FTC/TDF treatment arm had HBV DNA <69 IU/ml (p = 0.96). Rates of normal alanine aminotransferase (ALT) and normalised ALT were similar between groups (p = 0.41 and p = 0.97 respectively). Hepatitis B e antigen loss and seroconversion at week 240 were similar between groups, (p = 0.41 and p = 0.67 respectively). Overall, six patients achieved hepatitis B surface antigen (HBsAg) loss and one patient (FTC/TDF arm) had HBsAg seroconversion by week 240. No TDF resistance was observed up to week 240. Treatment was generally well tolerated, and renal events were mild and infrequent (similar to 8.6%). The mean change in bone mineral density at week 240 was -0.98% and -2.54% at the spine and hip, respectively. Conclusions: TDF monotherapy was effective and well tolerated in LAM-R CHB patients for up to 240 weeks. Lay summary: The goal of oral antiviral treatment for chronic hepatitis B (CHB) is to achieve and maintain undetectable HBV DNA levels. Treatment options with enhanced potency, and low risk of resistance development for patients infected with lamivudine resistant (LAM-R) HBV are required. Tenofovir disoproxil fumarate (TDF) monotherapy was effective and well tolerated without TDF resistance development in CHB patients with LAM-R, for up to 240 weeks.