Background: Human papillomavirus (HPV) vaccine may be commercially available in a few years. We explored the clinical benefits and cost-effectiveness of introducing an HPV16/18 vaccine in a population with an organized cervical cancer screening program. Methods: A computer-based model of the natural history of HPV and cervical cancer was used to project cancer incidence and mortality, life expectancy (adjusted and unadjusted for quality of life), lifetime costs, and incremental cost-effectiveness ratios (i.e., the additional cost of a strategy divided by its additional clinical benefit compared with the next most expensive strategy) associated with different cancer prevention policies, including vaccination (initiated at age 12 years), cytologic screening (initiated at 18, 21, 25, 30, or 35 years), and combined vaccination and screening strategies. We assumed that vaccination was 90% effective in reducing the risk of persistent HPV16/18 infections and evaluated alternative assumptions about vaccine efficacy, waning immunity, and risk of replacement with non-16/18 HPV types. Results: Our model showed that the most effective strategy with an incremental cost-effectiveness ratio of less than $60–000 per quality-adjusted life year is one combining vaccination at age 12 years with triennial conventional cytologic screening beginning at age 25 years, compared with the next best strategy of vaccination and cytologic screening every 5 years beginning at age 21 years. This triennial strategy would reduce the absolute lifetime risk of cervical cancer by 94% compared with no intervention. These results were sensitive to alternative assumptions about the underlying patterns of cervical cancer screening, duration of vaccine efficacy, and natural history of HPV infection in older women. Conclusions: Our model predicts that a vaccine that prevents persistent HPV16/18 infection will reduce the incidence of HPV16/18-associated cervical cancer, even in a setting of cytologic screening. A program of vaccination that permits a later age of screening initiation and a less frequent screening interval is likely to be a cost-effective use of health care resources.