OBJECTIVES: Under the circumstances of a severe pandemic and constrained research and manufacturing capacity, the need to appropriately deploy vaccination stockpiles becomes critical. The objective of this study was to provide insight into the most cost-effective vaccination strategy when under constrained circumstances. METHODS: A deterministic and compartmental SIR (Susceptible-Infected-Removed) cost-effectiveness model was developed from a US CDC perspective using Microsoft Excel. The model consists of 6 distinct age groups, integrated by a contact matrix. The infectivity of the pandemic was based on reported CDC estimates, with the model calibrated accordingly. A 75% vaccination efficacy was used, consistent with previous studies. Under the assumption of stockpiling 50 million doses of vaccine, vaccination strategies were assessed in terms of infections avoided during the estimated 17 month period of the pandemic. The scenarios included strategies targeted to specific age groups: individually targeted age groups, groups under 20, over 20, 20-59 and 0-12 and 60+ combined. Costs were limited to vaccine acquisition, with the total rate of vaccination per day estimated at 741,935. For the base case, we initiate the pandemic in May 2009 and began vaccination in October. Sensitivity analysis on the initiation of vaccination was also assessed. RESULTS: With no vaccination, a basic reproduction number of 1.3 and infectious period of 4.5 days yielded an attack rate of 27.7%.The cost-effectiveness of targeted vaccination ranged from $4.87 (13-19 years) to $67.05 (65+) per infection avoided. Under the criteria of exhausting vaccine supplies, the most cost-effective strategy was to target those under 20 years old ($10.77 per infection avoided). Initiating vaccination earlier during a pandemic marginally improved cost-effectiveness, while delayed vaccination resulted in substantially reduced cost-effectiveness. CONCLUSIONS: Administering vaccinations to those aged under 20 years is the most cost-effective strategy. All vaccination policies initiated after the peak of the pandemic, were less cost-effective.