The incidence of reported pertussis has increased during the past decade and poses a growing health and economic burden in developed countries, despite high rates of primary vaccination. Administration of a booster dose of acellular pertussis vaccine to adolescents may help reduce this burden, not only by reducing infections in vaccinated individuals but also by reducing transmission of Bordetella pertussis to other individuals, particularly infants. An epidemiologic model was created to assess the health and economic impact of implementing a program of routine acellular pertussis immunization in adolescents 11–18 years of age in the United States, considering both the reduction in cases in those vaccinated and among the unvaccinated population (due to herd immunity). Inputs for the base case were defined according to information derived from published literature and were supplemented by estimates provided by members of the Global Pertussis Initiative. Both direct and indirect costs were included (in 2002 US dollars) using U.S. data. Outcomes were evaluated over the lifetime of a cohort of potential adolescent vaccine candidates. Because of uncertainty in many of the inputs, extensive sensitivity analyses were conducted. With 80% vaccination coverage of adolescents and a 20% reduction of other cases because of herd immunity, >68,000 cases and 41 pertussis-related deaths would be avoided in the subsequent 10 years by routine administration of acellular pertussis boosters to a single cohort of adolescents in the United States. This strategy would be cost-effective, incurring from $6000 to $22,000 per life-year gained. The level of herd immunity attained and the true incidence of pertussis are critical determinants of cost effectiveness, as is the duration of immunity resulting from immunization. The cost of immunization and the discount rate also play a role. Although there is considerable uncertainty surrounding key inputs, the results indicate that the conditions required for adolescent immunization to be economically warranted are realistic.