OBJECTIVES: To perform a cost-effectiveness analysis of newborn universal vaccination against hepatitis B virus (HBV) and to identify the cost-effective affordability levels of the vaccination program in Vietnam. METHODS: We simulated a birth cohort using 1,693,000 newborns in 2002. Incremental cost-effective ratios (ICERs) per 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 used 5,000 Monte Carlo simulations to examine the cost-effectiveness acceptability and  affordability of the vaccination program from the payer’s perspective and to derive a cost-effective affordability curve to assess the program’s cost and health effects. All costs were expressed in 2002 US dollars. RESULTS: In the base-case scenario, newborn universal vaccination against HBV reduced the carrier rate by 58% at a cost of US$42 per carrier averted. From the payer’s perspective, marginal cost per life-year and per QALY gained were US$4.76, much lower than  GDP per capita of ~ US$440 in 2002. The vaccination could be potentially affordable starting at a relatively low budget of US$1.7 million. Newborn universal vaccination would save  US$ 1 billion from the treatment cost of complications due to chronic HBV infections. The probability of vaccination being both cost-effective and affordable is 27% at an annual budget of US$4.1 million at the cost-effectiveness threshold of US$3.9 per QALY. CONCLUSIONS: Universal newborn vaccination against HBV is highly cost-effective in Vietnam. In low-income, high-endemic countries, where funds are limited and economic results of vaccination are uncertain, our findings on the cost-effectiveness affordability options would assist decision-makers in making proper health investments in vaccination strategies against HBV.