Introduction: Human papillomavirus (HPV) are the causative agent of mucosal neoplasia. Both cervical, anal and oropharyngeal cancers incidence is constantly increasing, making the HPV infection, a significant worldwide concern. Together, the CD8+ T cytotoxic cell-mediated response and the HPV-specific antibody response control most of the HPV infections before the development of cancers. Areas covered: We searched the MEDLINE and EMBASE databases and identified 228 eligible studies from 1987 to 2019 which examines both naturally acquired and vaccine induced humoral immunity against HPV infection in female and male subjects from worldwide origin. Herein, we synthesize current knowledge on the features of systemic and mucosal humoral immunity against HPV. We discuss the issues of the balance between the viral clearance or the escape to the host immune response, the differences between natural and vaccine-induced HPV-specific antibodies and their neutralizing capability. We also discuss the protection afforded after natural infection or following prophylactic vaccination. Expert opinion: Understanding the antibody response induced by HPV infection has led to the design of first-generation prophylactic vaccines. Now, prophylactic vaccination induces protective and long-lasting antibody response which would also strengthened the natural moderate humoral response in people previously exposed to the virus.