OBJECTIVES: Cervical cancer is the third most common gynecologic cancer in the United States. Currently there are two proven approaches to cervical cancer prevention: conventional cytology screening and human papillomavirus (HPV) vaccination. Prevention guidelines recommend screening every one to three years after onset of sexual activity. In addition, many states have passed legislation to require mandatory HPV vaccination for school children. The study aims to compare the cost-effectiveness of HPV vaccination combined with conventional cytology screening versus HPV vaccination alone on cervical cancer prevention in the US. METHODS: A decision tree was used to estimate the lifetime costs (in 2004 US$) and outcomes for U.S. women receiving HPV vaccination or mandatory HPV vaccination combined with conventional cytology screening from the societal perspective. The costs and epidemiological data were derived from published literature and health institution websites. Outcomes included life expectancy and quality-adjusted life years (QALYs) gained. RESULTS: The incremental cost-effectiveness ratio (ICER) for HPV vaccination combined with the triennial screening compared to vaccination alone was $251,965 per QALY gained. The result was most sensitive to the total costs of conventional cytology screening. When the total costs of conventional cytology screening varied from $30 to $319, the ICER increased from $98,669 to $1,006,860 per QALY gained. When increasing the frequency of screening to biennial and annual, the ICER of HPV vaccination combined with screening compared to vaccination alone changed to $335,533 and $592,991 per QALY gained respectively. CONCLUSIONS: These results indicate that conventional cytology screening provides little benefit beyond that provided by HPV vaccination. They suggest that routine cytology screening should no longer be recommended for women who have been successfully vaccinated.