Preventive human papillomavirus (HPV) L1 vaccines are safe and efficient to prevent infection and lesions of vaccine- specific HPV types in women from 15 to 26 years, but also in older age groups. Clearly, public health funds are to be spent to organize programs for vaccination of young adolescents. Immunobridging studies and clinical trials have shown that HPV vaccines generate significantly higher plasma antibodies than following natural infections in women up to 55 years and prevent up to 90.5% (95% CI 73.7–97.5) vaccine-specific HPV infections and lesions in women aged 24–45 years who are HPV DNA-negative at the time of vaccination. However, data from clinical trials with HPV L1 vaccines in older women (older than 25 years) are still scarce compared to the amount of evidence from trials in women younger than 26 years. Information from large population-based studies indicates that older women remain at risk of infection by high-risk HPV and the risk of persistent high-risk HPV infection is significantly higher than in young women, leading to a higher risk of progressing disease and carcinoma. The natural history of HPV infection remains enigmatic as we do not know if the immune mechanisms that clear the HPV infection offer prolonged protection. On the contrary, some data indicate that seroconversion after a natural infection only partially protects against re-infection. Given the large proportions of adult men and women that change sexual partners, the protective effects of HPV L1 vaccines may offer an extra benefit against HPV-related genital diseases within a much shorter time period than after vaccination of prepubertal adolescents.