OBJECTIVES: Stockpiling pre-pandemic influenza vaccine could substantially mitigate the clinical and economic impact of an influenza pandemic. The aim was to develop a method for estimating cost outcomes associated with stockpiling pre-pandemic influenza vaccine versus no stockpiling, to inform healthcare decision-making in pandemic preparedness. METHODS: A probabilistic decision-analytic model was developed to examine the cost balance of stockpile acquisition (and maintenance) and cost-offsets from its use. Input parameters included data on pandemic factors, vaccine characteristics, the stockpile lifetime and associated costs. Base-case analysis for a fictional US city assumed a 3% annual probability of a pandemic with a clinical attack rate of 30%. Vaccine coverage was 50% of a population of 4.6M, with assumed effectiveness of 65% and antigen replacement after 3 years of a 5-year planning cycle. Costs per case of pandemic influenza were $2373 (2006 values) including direct costs and lost productivity. Discount rate was 3%. Assumptions were made on the impact of antivirals on the number of susceptibles. Sensitivity analyses were performed to address parameter uncertainty, including probability of a pandemic, attack rate, vaccine effectiveness and shelf-life, antiviral stockpile effectiveness and costs per case. RESULTS: In the base-case, total costs of a vaccine stockpile were US$78 million, offset by cost reductions of $124 million due to 50,000 fewer cases of influenza. This was analogous to the vaccine stockpile having a net present value of US$46 million. Tornado diagram analysis found the 3 main drivers in the model were, in order of importance, the pandemic probability, attack rate and cost per case. Multivariate probabilistic sensitivity analysis using Monte Carlo simulation found vaccine stockpiling to be associated with cost reductions in 71% of re-runs (-US$46 million 95% CI -US$217 million to US$51 million; 50,000 cases prevented 95% CI 10,000 to 130,000). CONCLUSIONS: Stockpiling pre-pandemic influenza vaccine should be considered an essential part of pandemic preparedness.