OBJECTIVES: Treatment options for chronic hepatitis B (CHB) are the direct inhibition of viral replication by continuous administration of nucleosides analogues (NUCs) or a finite 48-weeks course of peg-interferon (PEG). PEG can induce the off-therapy immune control of CHB leading to HBsAg loss/anti-HBs seroconversion but at a low success rate. On the other hand life-long treatment with NUCs is expensive. Exploiting the early identification of PEG-non-responders by combined HBV-DNA and HBsAg quantification at week-12 (stopping-rule), a new sequential therapeutic strategy may benefit both patients and payers. We measured the impact on the Italian National Health Service budget using the PEG-week-12-stopping-rule in the treatment of HBeAg-negative CHB. METHODS: A Markov model was developed over a 5 year horizon in the states: CHB, virologic response, relapse, HBsAg clearance, compensated and decompensated cirrhosis, hepatocarcinoma, liver transplant, post-liver transplant and death. The target population (treatment naïve CHB patients) was determined based on Italian national population forecasts and epidemiological data. The current mix of treatment with NUCs (entecavir, tenofovir, adefovir, lamivudine and telbivudine) and PEG (with no stopping rule) was compared with a mix based on a hypothetical uptake of PEG (with the stopping rule). The percentage of uptake from NUCs started at 25%, increasing over time. RESULTS: The estimated impact on the Italian NHS budget, over 5 years of treatment, resulted in a saving of approximately €74 million, 95% of which accounted for drug cost.  The beneficial impact of the stopping-rule became clear from the second year, when a  break-even point was reached. CONCLUSIONS: The large estimated savings in drug costs following the uptake of PEG + stopping-rule in the treatment of CHB HBeAg negative patients, together with previously published cost-effectiveness results, demonstrate a potentially advantageous profile of such a strategy, that could allow for more efficient use of health care resources.