ABSTRACT Objective: The aim of this study was to assess the cost-effectiveness of tenofovir disoproxil fumarate (TDF) in the treatment of chronic hepatitis B (CHB) versus alternative nucleos(t)ides from a UK National Health Service (NHS) perspective. Methods: A Markov model was used to calculate costs and benefits ofnucleos(t)ide strategies in hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients with hepatitis B virus mono-infection and compensated liver disease. The model included 18 disease states representing CHB progression. Quality-of-life data and costs for severe disease states were based on publishedstudies, while monitoring costs for other disease states were based on expert opinion. Transition probabilities for movements between states were based on a meta-analysis, clinical trials, and natural history studies. Results: First-lineTDF generated the highest net benefits of all 211 nucleos(t)ide strategies evaluated at a threshold of pound20,000 per quality-adjusted life-year (QALY) gained. First-line TDF cost pound19,084/QALY gained compared with giving lamivudine (LAM) first-line and switching to TDF when LAM resistance occurs. First-line TDF was also more effective and less costly than first-line entecavir(ETV), and showed extended dominance over first-line adefovir and strategies reserving adefovir, ETV, or combination therapy until after LAM resistance develops. For patients who have developed LAM resistance, TDF was also the most cost-effective treatment, generating greater net benefits than any other second-line strategy. Conclusions: First-line TDF is the most cost-effective treatment for patients with CHB at a pound20,000 to pound30,000/QALY ceiling ratio, costing pound19,084/QALY gained compared with the next best alternative.