OBJECTIVES: To perform a cost-effectiveness analysis of universal newborn vaccination against hepatitis B virus (HBV) and to identify the affordability of the programme in Viet Nam, a highly endemic country of HBV infection. METHODS: Marginal cost of every life-year and quality-adjusted life-year (QALY) gained with universal newborn vaccination against HBV was calculated using a Markov model. Two types of analyses (including and excluding expenditure on the treatment of chronic hepatitis B and its complications) were performed. We conducted one-way sensitivity analyses to confirm the robustness of the results. We used Monte Carlo simulations to examine the affordability of the vaccination programme from payer’s perspective to derive an affordability curve for the programme. RESULTS: In the base-case scenario, universal newborn vaccination against HBV reduced the carrier rate by 72%, and increase number of life years and QALY gained of a  2008 birth cohort by 1.8 years (71.21 years vs. 69.41 years) and 2.26 years (71.03 years vs. 68.77 years), respectively. Marginal cost per life-year and per QALY gained were US$ 18.82 and US$ 13.16, much lower than the annual GDP per capita of around US$ 1,024). The probability of the vaccination programme to be both cost-effective and affordable is 60% at an annual programme cost of US$ 253,000 (from the payer’s perspective), where the threshold cost-effective value is US$ 13.16 per QALY gained. CONCLUSIONS: Universal newborn vaccination against HBV is highly cost-effective in Viet Nam. As a low-income, endemic country where funds are limited and economic results of vaccination are uncertain, affordability options allow decision-makers to make proper health investment in vaccination strategies against HBV. In the long run, adolescents should also be universally vaccinated against HBV.