OBJECTIVES: The analysis aimed to evaluate the cost-effectiveness of 48-week therapy with peginterferon alpha-2a (PegIFNα-2a) in HBeAg-positive chronic hepatitis B (CHB) patients versus 48-week (short-term analysis) or 4-year (long-term analysis) therapy with adefovir, entecavir or lamivudine from the public payer perspective in Poland. METHODS: A life-time Markov model based on previously published analysis was used. States encompassed treatment response (HBeAg seroconversion), relapse, complications (compensated/decompensated cirrhosis, hepatocellular carcinoma, liver transplantation) and death. Quality-adjusted life years (QALYs) were the measure of effectiveness. Short-term efficacy assessment was based on the results of randomized clinical trials (RCTs). Long-term efficacy data for nucleos(t)ide analogues (NAs) were derived from published models and RCTs extensions. Utilities and transition probabilities (spontaneous response, relapse, complications, death) were taken from published literature. Direct medical costs, i.e. costs of drugs and procedures used in the treatment of CHB and its complications were obtained using a survey conducted among Polish clinicians. In the base case analysis costs and benefits were discounted at a 5% and 3.5% annual rate, respectively. The robustness of the results was assessed using one-way, scenario and probabilistic sensitivity analyses. RESULTS: In both the short and long-term analysis PegIFNα-2a increased number of QALYs and life years gained (LYGs) compared to all investigated NAs. In the short-term model PegIFNα-2a decreased the costs of complications’ treatment and increased the overall costs due to drug acquisition cost. ICER for PegIFNα-2a vs. lamivudine, adefovir and entecavir amounted to 50,809, 11,442 and 39,588 PLN/QALY, respectively (1€≈4 PLN). In the long-term model costs of NAs were higher. PegIFNα-2a was cost-saving and dominated adefovir and entecavir, while ICER versus lamivudine amounted to 27,431 PLN/QALY. Sensitivity analysis proved these results to be robust. CONCLUSIONS: Peginterferon alfa-2a is cost-effective when compared to adefovir, entecavir and lamivudine in Poland.