OBJECTIVES: In the United States (U.S.), approximately 79 million persons are infected by HPV with 14 million new infections occurring each year. A quadrivalent HPV vaccine, which offers protection against genital warts and HPV-related cancers, is currently administered in three doses. Clinical trial evidence showed non-inferiority of a two-dose vaccine, but with no evidence beyond four years of vaccination. Modeling studies have indicated requiring a third-dose if a two-dose vaccine offers protection for only 10 years. This study evaluates the cost-utility of two different dosing schedules for HPV vaccination in women in the U.S. METHODS: A Markov model was developed in TreeAge Pro using a hypothetical cohort of 100,000 HPV unvaccinated, uninfected 12-year old girls, assessing lifetime costs and utilities associated with no vaccination, or vaccination with two or three doses. Markov states included well, CIN stages, post-year one cancer stages and death as the absorbing state. Transition states included HPV disease progression and consequences (genital warts, pre-cervical CIN transitions, and HPV-related cancers). Variable dosing effectiveness, transition probabilities for disease progression, costs, utilities, and disease incidence were derived from targeted literature searches. Vaccine efficacy data was obtained from the Food and Drug Administration (FDA) approved vaccine package insert. Sensitivity analyses were conducted to evaluate parameter uncertainty. RESULTS: The lifetime costs for the three and two-dose schedules were $30,116.82 and $30,563.86, and total QALYs accrued were 60.3113 and 60.3087 respectively. The three-dose schedule dominated the two-dose schedule and no vaccination.  The model results were most sensitive to dose-based vaccine efficacy offering protection against HPV types 16 and 18, CIN stage utilities and CIN3 treatment costs, in the sensitivity analysis. CONCLUSIONS: A three-dose vaccination schedule is associated with better health outcomes at a lower total cost.  Based on this analysis, the three-dose option is the preferred strategy and should be employed when possible.