This study addresses the tradeoff between Vietnam’s national poultry vaccination program, which implemented an annual two-round HPAI H5N1 vaccination program for the entire geographical area of the Red River Delta during the period from 2005–2010, and an alternative vaccination program which would involve vaccination for every production cycle at the recommended poultry age in high risk areas within the Delta. The ex ante analysis framework was applied to identify the location of areas with high probability of HPAI H5N1 occurrence for the alternative vaccination program by using boosted regression trees (BRT) models, followed by weighted overlay operations. Cost-effectiveness of the vaccination programs was then estimated to measure the tradeoff between the past national poultry vaccination program and the alternative vaccination program. Ex ante analysis showed that the focus areas for the alternative vaccination program included 1137 communes, corresponding to 50.6% of total communes in the Delta, and located primarily in the coastal areas to the east and south of Hanoi. The cost-effectiveness analysis suggested that the alternative vaccination program would have been more successful in reducing the rate of disease occurrence and the total cost of vaccinations, as compared to the national poultry vaccination program.