An AS04-adjuvanted human papillomavirus (HPV)-16/18 vaccine has demonstrated excellent efficacy for up to 6.4 years in preventing related persistent infections and cervical precancerous lesions in both Phase II and Phase III clinical trials. The immune responses induced by HPV vaccination are different to those after natural infection. The virus has learned to largely evade our immune system through centuries of co-evolution with the consequence that the immune responses after natural infection, aiming to control or eradicate the virus, are attenuated. However, the AS04-adjuvanted HPV prophylactic vaccine, designed with a new Adjuvant System approach, is able to improve upon the natural immune responses to the virus as it induces strong and sustained neutralizing antibody levels that are several times higher than after natural infection, while creating immune memory through higher frequency of memory B cells. These immunological effects represent the basis for the protection afforded by the AS04-adjuvanted HPV-16/18 vaccine and its observed long-term efficacy against development of precancerous lesions to prevent cervical cancer.