We present a transmission dynamic model that can assess the epidemiologic consequences and cost-effectiveness of alternative strategies of administering a prophylactic quadrivalent (types 6/11/16/18) human papillomavirus (HPV) vaccine in a setting of organized cervical cancer screening in the United States. Compared with current practice, vaccinating girls before the age of 12 years would reduce the incidence of genital warts (83%) and cervical cancer (78%) due to HPV 6/11/16/18. The incremental cost-effectiveness ratio (ICER) of augmenting this strategy with a temporary catch-up program for 12- to 24-year-olds was US $4,666 per quality-adjusted life year (QALY) gained. Relative to other commonly accepted healthcare programs, vaccinating girls and women appears cost-effective. Including men and boys in the program was the most effective strategy, reducing the incidence of genital warts, cervical intraepithelial neoplasia, and cervical cancer by 97%, 91%, and 91%, respectively. The ICER of this strategy was $45,056 per QALY.