INTRODUCTION: Countries like Vietnam transitioning to middle-income status increasingly bear the cost of both existing and new vaccines. However, the impact and cost-effectiveness of the Expanded Programme on Immunization (EPI) as a whole has never been assessed on a country level. METHODS: Data on vaccine-preventable disease incidence and mortality from Vietnam's national surveillance was analysed to estimate the likely impact that vaccination in 1980-2010 may have had. Adjustment for under-reporting was made by examining trends in reported mumps incidence and in case-fatality risks for each disease. The same data were separately analysed using the Lives Saved Tool (LiST) to give an alternative estimate of impact. The financial cost of EPI in 1996-2010 was also estimated from the perspective of service provider. RESULTS: National surveillance data suggests that up to 5.7 million diseases cases and 26,000 deaths may have been prevented by EPI. Analysis using LiST suggests that even more deaths (370,000) may have been prevented by measles and pertussis vaccination alone. The cost-effectiveness of EPI is estimated to be around $1000-$27,000 per death prevented. CONCLUSION: Two separate approaches to assessing EPI impact in Vietnam give different quantitative results but a common conclusion: that EPI has made a substantial impact on mortality and represents good value for money.