OBJECTIVES:: Colombia currently offers a three-dose human papillomavirus (HPV) immunization program, however compliance with all three doses has been challenging. The relative cost-effectiveness of the AS04-HPV-16/18 vaccine (AS04-HPV-16/18v) versus HPV-6/11/16/18 vaccine (4vHPVv) given in a two-dose schedule is assessed. METHODS:: A static lifetime cohort Markov model accounting for the natural history of low-risk and oncogenic HPV infection, screening effects, and vaccination in 11-year-old girls was used. The healthcare provider perspective was used. Vaccine efficacy, including cross-protection profiles of both vaccines, was derived from the literature. Outcomes and costs were discounted by 3% per year. RESULTS:: The model estimated that at 90% coverage, vaccination with AS04-HPV-16/18v would result in 778 additional life-years gained, 98 additional cervical cancer (CC) cases averted, and 46 additional deaths avoided compared with 4vHPVv (undiscounted). AS04-HPV-16/18v was expected to generate total cost-savings of US$1,770,800 with 28.6 additional quality-adjusted life-years gained (discounted; dominant choice). The base case analysis reflected the effect of higher cross-protection levels provided by AS04-HPV-16/18v against non-vaccine oncogenic HPV types, providing broader protection against cervical intraepithelial neoplasia (CIN) and CC. Greater reduction in treatment costs pertinent to CIN and CC with AS04-HPV-16/18v outweighed the greater reduction in genital wart costs with 4vHPVv in the base case scenario. When higher treatment costs of genital warts were considered in a sensitivity analysis, AS04-HPV-16/18v was not cost-effective compared with 4vHPVv. In contrast, 4vHPVv dominated AS04-HPV-16/18v when no cross protection scenarios were considered. CONCLUSIONS:: Our results indicate that two-dose immunization with AS04-HPV-16/18v provides additional health benefits compared with 4vHPVv, due to its greater cross-protection against oncogenic HPV types. These benefits outweigh in terms of costs those provided by 4vHPVv when reducing low-risk HPV protection (e.g., genital warts). Also, implementation of a two-dose HPV vaccination schedule in Colombia has the potential to improve compliance compared with the current three-dose schedule.