In Colombia, the human papillomavirus (HPV) vaccine was launched in 2012 in the context of a school-based national vaccination program targeting girls ages 9 to 14 and offering catch-up vaccination for girls ages 14 to 17. In this study, we evaluated the program's impact on type-specific HPV infection by comparing HPV cervical prevalence among vaccinated and nonvaccinated women. This is a comparative cross-sectional study conducted 5 years after the quadrivalent HPV vaccination implementation in a sentinel Colombian City. This study included young women (18-25 years old) who had been vaccinated in the catch-up group and were attending universities and technical institutions, and women who attended primary health care facilities for Pap smear screening. The HPV prevalence of 1,287 unvaccinated women was compared with the prevalence of 1,986 vaccinated women. The prevalence of HPV16/18 infections was significantly lower in vaccinated compared with unvaccinated women (6.5% vs. 15.4%; P < 0.001), whereas for HPV6/11 infections, a decrease of 63.7% in vaccinated women (1.02% vs. 2.81%) was observed. The adjusted effectiveness to HPV16/18 was 61.4%; 95% CI, 54.3%-67.6%. However, the effectiveness against HPV16/18 was significantly higher among women vaccinated before their sexual debut 91.5%; 95% CI, 86.8-94.5, compared with effectiveness for vaccination after their sexual debut, 36.2%; 95% CI, 23.6-46.7. Five years after the introduction of HPV vaccines in Colombia, high effectiveness of HPV to prevent HPV16/18 infections is observed in the catch-up cohorts including virgin and sexually active women. PREVENTION RELEVANCE: Monitoring HPV vaccines post-licensure plays an important role in assessing the progress of immunization programs, demonstrating the impact of vaccines on the population, and providing data for policy needs. In Colombia, HPV vaccines showed effectiveness when administered before start of sexual activity, and two doses are sufficient to achieve good protection.