Introduction: Although human papillomavirus (HPV) routine vaccination programmes have been implemented around the world and recommendations have been expanded to include other high-risk individuals, current recommendations often differ between countries in Europe, as well as worldwide. Aim: To find and summarise the best available evidence of HPV vaccination in high-risk patients aiding clinicians and public health workers in the day-to-day vaccine decisions relating to HPV in Spain. Methods: We conducted a systematic review of the immunogenicity, safety and efficacy/effectiveness of HPV vaccination in high-risk populations between January 2006 and June 2016. HPV vaccination recommendations were established with levels of evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Results: A strong recommendation about HPV vaccination was made in the following groups: HIV infected patients aged 9–26 years; men who have sex with men aged 9–26 years; women with precancerous cervical lesions; patients with congenital bone marrow failure syndrome; women who have received a solid organ transplant or hematopoietic stem cell transplantation aged 9–26 years; and patients diagnosed with recurrent respiratory papillomatosis. Conclusions: Data concerning non-routine HPV vaccination in populations with a high risk of HPV infection and associated lesions were scarce. We have developed a document to evaluate and establish evidence-based guidelines on HPV vaccination in high-risk populations in Spain, based on best available scientific evidence.