OBJECTIVES: HPV epidemiology and screening practices vary considerably between countries and specific analyses are required to estimate the impact of prophylactic cervical cancer vaccination. This study adapted a health economic model to Italy to predict the clinical and economic impact. METHODS: A Markov model based upon the natural history of HPV and cervical cancer was developed to simulate transitions between health states (normal, HPV, Cervical Intraepithelial Neoplasia stages 1 to 3, Cervical Cancer (CC) stages 1 to 4, and death) in the presence of specific screening programs. Italian data was used to for costs, and screening and treatment practices, and published clinical data was used to estimate efficacy against oncogenic HPV types 16, 18, 31, 45. The model was calibrated to Italian epidemiological data including age-specific HPV prevalence, prevalence of CIN lesions, CC incidence and mortality. The cost-effectiveness of vaccination against HPV for cohorts of different ages was assessed using the calibrated model. RESULTS: With 100% vaccine coverage, in a 12 year old cohort of females there is estimated to be a 68% reduction in the prevalence of high-grade precancerous lesions due to oncogenic HPV, and a 78% and 79% reduction in cervical cancer cases and deaths, respectively. Vaccination would also produce substantial reductions in these outcomes for the 18 and 25 year old cohorts, and in the number of screening tests and treatments required. With 3% discount rates on costs and outcomes, vaccination is cost effective in cohorts of 12, 18, and 25 year olds with estimated cost per QALYs of €30,624, €31,078, and €31,116 respectively. CONCLUSION: The model was successfully adapted to represent Italian epidemiological data, screening and treatment practices and predicted a substantial long-term benefit of prophylactic cervical cancer vaccination. The vaccine may be considered to be cost-effective under a number of assumptions and vaccination age groups.