To optimally develop or adjust national contingency plans to respond to the next influenza pandemic, we developed a decision type model and estimated the total health burden and direct medical costs during the next possible influenza pandemic in the Netherlands on the basis of health care burden during a regular epidemic. Using an arithmetic decision tree-type model we took into account population characteristics, varying influenza attack rates, health care consumption according to the Dutch health care model and all-cause mortality. Actual direct medical cost estimates were based on the Dutch guidelines for pharmaco-economic evaluation. In the base-case scenario with no preventive measure available and an average influenza attack rate of 30%, 4,958,188 influenza infections, 1,552,687 GP consultations, 83,515 hospitalizations and 173,396 deaths will take place in The Netherlands. The burden is highest in adults aged 20 to 64 years. If minimizing the total mortality and sustaining highest net economic returns is the objective, this group needs to be targeted in interventions.