Chronic Hepatitis B (CHB) is caused by chronic infection with Hepatitis B Virus (HBV) and represents a major global health problem. Traditional CHB treatments are lamivudine (LAM) and interferon alfa-2a (IFN). Peginterferon alfa-2a (PEG) has been recently approved for the treatment of CHB disease. OBJECTIVES: To assess the economic and clinical impact of the use of peginterferon alfa-2a (40KD) versus LAM for the treatment of HBeAg-negative CHB and versus IFN for the treatment of HBeAg-positive CHB disease in Italy. METHODS: The CHB disease course was simulated with the use of a Markov model. The simulation was prolonged over a cohort's lifetime. Comparative evaluation of PEG vs. LAM was based on a recent phase III clinical trial in HBeAg-negative CHB. Comparative evaluation of PEG vs. IFN was based on a phase II clinical trial comparing the two treatments in HBeAg-positive CHB. Considered scenarios were: 48-week PEG vs LAM treatment; 48-week PEG vs 4-year LAM; 24-week PEG vs. IFN. Clinical outcomes measured were average life years gained (LYs) and quality-adjusted life years (QALYs). Direct costs were considered and valued according to current Italian national prices, tariffs and published literature. Deterministic and probabilistic sensitivity analyses were performed and acceptability curves generated. Costs and outcomes were discounted at a 3.5% annual rate. RESULTS: 0.82, 0.68, and 0.26 discounted QALYs per patient are gained with PEG vs 48-week LAM, 4-year LAM and IFN, respectively. Discounted incremental costs per patient are € 7,021, € 5,725, and € 2,304. Corresponding cost-effectiveness and cost-utility ratios are 9,440 €/LY and 8,603 €/QALY, 9,218 €/LY and 8,368 €/QALY, 9,575 €/LY and 8,714 €/QALY. CONCLUSIONS: The use of peginterferon alfa-2a (40KD) in CHB patients, as compared with current practice, has the potential of improving clinical outcomes with a cost per LY and QALY gained below that of universally accepted therapies.