OBJECTIVES: Meningococcal disease can have severe consequences, and outbreaks require immediate outlay of resources. Menactra, a new conjugate vaccine for meningococcal disease, provides protection against serogroups A, C, Y and W-135. This study examines the cost-effectiveness of routinely vaccinating adolescents in the US with Menactra. METHODS: The economic implications of meningococcal disease vaccination in the US were assessed using a discrete event simulation. These analyses compare routine vaccination of 12-year-olds with Menactra to no routine vaccination. Both the direct benefits of vaccination and the indirect ones resulting from herd immunity are modeled. The impact of vaccination on outbreaks of disease is also modeled. Outcomes include cases, deaths, sequelae, life years lost, quality adjusted life years (QALYs) lost and both direct and indirect costs (2003 USD). In the base case, the vaccine price was $70. Vaccine efficacy was assumed to be 90% over 10 years. All outcomes are discounted at 3% per annum. RESULTS: Without vaccination, there is an average of 2808 cases per year and 375 deaths. A total of 2.9 community-based and 6.1 school-based outbreaks per year are predicted. The cost of meningococcal disease averages $311 million per year. Routine vaccination reduces the number of cases to under 2000, deaths to 230, community outbreaks to 0.7 and school-based outbreaks to 1.7. Disease costs are reduced by over $100 million, but vaccination increases total costs, resulting in a cost per discounted QALY gained of $36,868. Sensitivity analyses reveal that outcomes are strongly influenced by the duration of protection conferred on those vaccinated, and the extent of herd immunity resulting from routine immunization. CONCLUSION: Vaccinating adolescents in the US with Menactra will reduce burden of disease and can be cost-effective. Outcomes should be reevaluated as more data become available.