BACKGROUND: Vaccines have demonstrated cost-effectiveness in managed care through the prevention of disease. As new vaccines for previously untargeted conditions are developed, pharmacoeconomic modeling is becoming even more critical for the quantification of value in the health care industry. Two recently developed vaccines aimed at prevention of infection from human papillomavirus (HPV) types 16 and 18 have proven to be highly efficacious. HPV 16 and 18 are the 2 most common oncogenic strains of HPV and are responsible for 70% of cervical cancer cases worldwide. Persistent infection with an oncogenic HPV type is a known cause of cervical cancer. Therefore, prevention of cervical cancer via HPV vaccination may have a significant financial impact. OBJECTIVE: To qualitatively review existing mathematical models of the cost effectiveness of prophylactic HPV vaccination, with an emphasis on the impact on managed care in the United States. METHODS: Mathematical models of the cost-effectiveness of HPV vaccination based on U.S. data were reviewed. A search of the PubMed database was conducted using the search terms "HPV," "vaccine," and "cost-effectiveness" for articles published before February 22, 2010. Studies employing mathematical models to estimate the cost-effectiveness of HPV vaccination in healthy subjects from the United States were included. Models based on data or populations from outside of the United States were excluded. Outcomes were measured with incremental cost-effectiveness ratios (ICERs), typically in units of quality-adjusted life expectancy (quality-adjusted life years [QALYs] gained). Most studies included in this review modeled vaccination of a cohort or population of females aged 12 years. Assessment of catch-up vaccination in females (through aged 24 to 26 years) was included in a couple of reports. One study examined vaccination in older females (aged 35, 40, and 45 years). Models typically compared a strategy of HPV vaccination with the current practice of cervical screening (sampling of cervical cells for disease detection) alone. RESULTS: 11 studies of cost-effectiveness modeling of HPV vaccination were included in this review. A direct quantitative comparison of model results is challenging due to the utilization of different model types as well as differences in variables selected within the same model type. Each model produced a range of cost-effectiveness ratios, dependent on variables included in sensitivity analyses and model assumptions. Sensitivity analyses revealed the lowest ICER to be $997 per QALY gained and the highest ICER to be $12,749,000 per QALY gained. This enormous range highlights the need to clarify what model assumptions are being made. The 2 studies that included modeling of catch-up vaccination scenarios in females older than age 12 years also produced a wide range of ICERs. One study, assuming 90% efficacy, 100% coverage, and lifelong immunity, modeled catch-up vaccination in all females aged 12 to 24 years and yielded an ICER of $4,666 per QALY. If the duration of protection was limited to 10 years, then costs increased to $21,121 per QALY. The other study modeling catch-up HPV vaccination assumed 100% efficacy, 75% coverage, and lifelong immunity. ICERs in this study for outcomes relating to cervical cancer ranged from $43,600 per QALY in the base model vaccinating only 12 year olds with no catch-up vaccination, to $152,700 in a model including catch-up vaccination through age 26 years. Although catch-up to age 21 years resulted in a cost of $120,400 per QALY, the ICER decreased to $101,300 per QALY if model outcomes related to prevention of genital warts were also included. The lone study modeling vaccination in women aged 35 to 45 years resulted in an ICER range of $116,950 to $272,350 per QALY when compared with annual and biennial cytological screening. Cost-effectiveness was defined as an ICER at or below $100,000 per QALY gained. All models of female adolescent vaccination were able to produce vaccination strategies that would be cost-effective according to this definition in addition to many strategies that would be cost-prohibitive. Variables influential in determining cost-effectiveness of HPV vaccination included the frequency of accompanying cervical screening, the age at which screening is initiated, vaccination efficacy, duration of vaccine protection, and the age range of females to be vaccinated. The actual effectiveness of HPV vaccination in the female population will also depend on levels of vaccine uptake or coverage and compliance in completing all vaccine doses. CONCLUSION: Clinical studies have shown HPV vaccination to be highly efficacious and potentially lifesaving if administered to females naive or unexposed to vaccine HPV types. Modeling studies have also shown that HPV vaccination can be cost-effective with an ICER of $100,000 or less per QALY gained if administered to females aged 12 years in the context of cervical screening intervals typically greater than 1 year. Catch-up vaccination through 21 years of age increases the cost per QALY to more than $100,000. Until real-world coverage rates increase, cost-effectiveness modeling of HPV vaccination underestimates the actual cost per QALY.