OBJECTIVES: HPV DNA has been detected in up to 99.7% of all cervical cancers, and infection with 2 types (HPV-16, 18) accounts for more than 50% of cases. We developed a computer-based Markov model of the natural history of HPV infection and cervical carcinogenesis to project the impact of a prophylactic vaccine against HPV 16/18 infection on the age-specific incidence and lifetime risk of invasive cervical cancer, precursor cervical lesions, and type-specific infection with HPV. METHODS: A comprehensive literature review was conducted to define plausible ranges for parameter values and the model was then calibrated to the best available population-based data. We explored the impact of alternative assumptions about vaccine efficacy, waning immunity, and competing risks associated with non-16/18 HPV types in vaccinated women. RESULTS: The model predicted a peak age-specific cancer incidence of 90 per 100,000 in the 6th decade, a lifetime cancer risk of 3.7%, and a reproducible representation of type-specific HPV within precancerous lesions and cervical cancer. A vaccine that prevented 98% of persistent HPV 16/18 was associated with an approximate equivalent reduction in 16/18-associated cancer and a 51% reduction in total cervical cancer. A vaccine that prevented 75% of persistent HPV 16/18 was associated with a 70% to 83% reduction in 16/18-associated cancer cases. Several modeling assumptions were identified that resulted in amplification or blunting of the vaccine's effect on outcomes - however, when the vaccine was either very ineffective (e.g., less than 20% efficacy) or very effective (e.g., more than 80% efficacy), the differences in projected outcomes associated with these were minimal. CONCLUSIONS: A prophylactic vaccine that prevents persistent HPV 16/18 infection can be expected to significantly reduce HPV-16/18-associated LSIL, HSIL and cervical cancer.