Background: During the first large outbreak of avian influenza (H5N1) in 2004 in Vietnam, an estimated 45 million poultry were culled or died, which resulted in a direct loss of approximately 0.1 percentage points of GDP (World Bank, 2005). The need for an effective strategy is not only the concern of biology and medical science but also of epidemiology. Methodology: We use a mathematical model to estimate the transmission probability of the disease based on daily reported number of dead poultry in northern Vietnam in November of 2005. The estimated values then are applied in an agent-based model which is used to evaluate the efficiency of current under-taken control measures. Result: The results imply a combination of culling 10% of infected poultry, 50% of preventive vaccinating and limiting transport of poultry, poultry products when 1% of the population were reported infectious could keep the disease under control and halt the infection process within 65 days. Conclusion: To prevent a new major outbreak of avian influenza in domestic poultry, a comprehensive strategy of culling, bio-security control and large-scale vaccination campaign should be set up in motion.