With a human papillomavirus (HPV) vaccine soon to become available for widespread use, several studies have modelled the cost-effectiveness of vaccination. These pioneer studies are likely to be influential on the design of further analyses, and we have therefore summarised and critically reviewed the strengths and limitations of their methods and assumptions. Despite a lack of transparency in some key elements, the most influential assumptions were identified as relating to vaccine effectiveness, cervical screening, and model design. Although the studies suggest that the introduction of an HPV vaccine could be cost effective compared with current practice in the USA, there is still substantial uncertainty around key variables, and model validation seems insufficient. The desirability of vaccinating boys in addition to girls has been explored in only one study. Further refinements to model design and epidemiological variables of (type-specific) HPV disease progression, and expansions on the options for vaccine use, are required for policy making.