Chronic hepatitis B infection represent a significant disease burden in Argentina and worldwide. New therapeutic strategies are emerging, including entecavir, a nucleosid analogue. The objective of the present study was to evaluate the cost-effectiveness of entecavir vs. lamivudine in Argentina (both in HBeAg positive and negative patients). Thus, a decision model that incorporated the main health outcomes associated to chronic hepatitis B infection was used, from the main Argentina's health system and social perspectives over a ten years time horizon. We combined efficacy data from randomized controlled trials, relative risk of long-term disease-related complications from observational studies, and life tables from Argentine vital statistics. Cost included those of drugs, clinical events and their complications. One way sensitivity analyses were performed to evaluate uncertainty. Entecavir showed a higher reduction in viral load than lamivudine, that implied fewer disease complications such as compensated cirrhosis, decompensated cirrhosis and hepatic carcinoma. HBeAg positive and negative patients treated with entecavir (discounted results) had 0.49 and 0.57 years of life gained and 0.44 and 0.51 quality of life adjusted years gained per patient in comparison with lamivudine. Results were robust, and showed that the most influential parameter was that of entecavir cost. Finally, entecavir showed to be from "cost-saving" to "cost-effective" according to the perspective.