OBJECTIVES: Chronic hepatitis B (CHB) treatment necessitate, according to European guidelines, to use potent antiviral agents with optimal resistance profiles. Increased healthcare financial burden means physicians, payers and decision makers need to evaluate CHB treatment cost-effectiveness. This model aims to estimate the medical cost savings of treating nucleoside-naïve CHB patients with a potent antiviral agent, from a French payer’s perspective METHODS: CHB was simulated using a disease-state transition model with states defined as mild fibrosis (Ishak F0/F1), significant fibrosis (F2–F4), advanced fibrosis/cirrhosis (>F4) and complicated states (decompensated cirrhosis (DC), hepatocellular carcinoma (HCC), liver transplant and death) based on available natural history data. The model assumed a 5-year entecavir treatment and 30-year follow-up and was based on available clinical data. The transition probabilities between states increased with detectable viral load levels and varied by HBeAg status. Direct medical costs included CHB and liver complications management. The primary model output is the estimated cost avoided per patient per day of treatment, compared to no treatment in nucleoside-naïve CHB patients RESULTS: Progression to HCC, liver transplant or death was estimated at 76% for untreated patients compared to 31% for entecavir patients, while the progression to DC, HCC, liver transplant or post-liver transplant resulted in annual costs/patient of €9,718 [95% confidence interval (CI): 8,260; 11,175], €5,066 [4,306; 5,826], €87,105 [74,039; 100,171] and €19,421 [16,508; 22,335], for 2008, respectively . Cost of not treating CHB patients was estimated at €16.4/day (average over patient lifetime). Entecavir treatment translated into specific patient benefit with an estimated cost saving of €1.2/day of entecavir treatment (95% CI: ‑9.6; 4.6).  CONCLUSIONS: Treatment of CHB using a potent antiviral agent with high genetic barrier to resistance, such as entecavir, is cost-effective as associated with improved clinical outcomes and lower healthcare costs compared with no treatment.