OBJECTIVES: To estimate the cost-effectiveness of available treatments for CHB in  HBeAg-negative and HBeAg-positive patients in Spain. METHODS: A Markov model was used to project, over the next 30 years, the HBV-related complications and future costs of consecutive cohorts of CHB patients in Spain treated with adefovir, entecavir, lamivudine, pegylated interferon, telvibudine and tenofovir. A second line combination therapy (lamivudine+adefovir) was assigned for patients resistant to any first-line oral antiviral option, whilst patients not responding to oral treatments where assumed to discontinue therapy and experience the risk of disease complications, as described by the natural history of CHB. Patients not responding to pegylated interferon were assumed to start an oral treatment –tenofovir or entecavir- with corresponding costs and effects. The probabilities of disease progression were based on HBV-DNA levels for each treatment option in the model and were obtained from data published in the literature. Disease and complications costs were based on the healthcare payer perspective at a local level (the Spanish National Health System). An annual 3% discount rate was applied to future costs and outcomes (quality adjusted life years – QALY). RESULTS: The higher rate of patients with undetectable HBV-DNA with tenofovir translated to its higher effectiveness in terms of QALY, followed by pegylated interferon, entecavir, telbivudine, lamivudine and adefovir in HBeAg-positive patients and pegylated interferon, entecavir, telbivudine, adefovir and lamivudine in HBeAg-negative patients. Tenofovir presented higher effectiveness and lower costs than entecavir and telbivudine in HBeAg-negative patients (besides pegylated interferon in HBeAg-positive patients), and cost-effectiveness ratios with respect to the rest of therapies far below the common reference efficiency threshold of €30,000 per QALY in Spain. CONCLUSIONS: In chronic HBV infected patients, tenofovir is a cost-effective or even a dominant (lower cost and (higher efficacy) strategy in comparison to the rest of available therapies for CHB in Spain.