OBJECTIVES: Prescribers, payers and health care decision-makers operating in diverse health care settings are increasingly examining the value of innovative treatments. The analysis aims at estimating the relative value of the two preferred first-line oral antiviral treatment options for chronic hepatitis B (CHB) according to the EASL guidelines: entecavir (ETV) and tenofovir (TDF) from a Spanish payer’s perspective. METHODS: Hepatitis B disease was simulated using a health-state transition model with disease-states defined as mild disease (Ishak F0/F1), fibrosis (F2–F4) and advanced fibrosis/cirrhosis (>F4), and complicated disease-states (decompensated cirrhosis, hepatocellular carcinoma, liver transplant and death) based on available natural history data. The value of treatment-specific attributes on disease progression/regression was estimated from clinical practice data in real world settings in terms of lifetime events and costs avoided. Treatment attributes included: additional testing requirements at treatment initiation and required renal function monitoring; adverse events per product labelling; reversal of fibrosis; and treatment intensification in case of suboptimal viral suppression to avoid potential resistance. A 5-year treatment duration was assumed. Primary model output is the estimated cost avoided per-patient per day of treatment, associated with the clinical attributes of ETV compared to TDF in the treatment of nucleoside-naïve HBeAg-positive and -negative CHB patients RESULTS: The daily cost of antiviral therapy for a CHB patient was estimated at €13.2 for ETV compared to €9.6 with TDF. Lifetime treatment cost avoided due to ETV’s clinical attributes was quantified at €3.6 [95% confidence: interval: 2, 5.2] per day of therapy. CONCLUSIONS: Estimating total treatment cost-avoidance associated with specific clinical attributes is a novel approach in assessing the value of treatment options. ETV exhibits the characteristics of a favourable CHB treatment option, which directly translates into economic and therapeutic added value.