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Human papillomavirus (HPV) vaccination prevents the development of HPV-associated malignancies. Adolescent and young adult survivors of childhood cancers and patients with sickle cell disease (SCD) are vulnerable patient populations who would significantly benefit from HPV vaccination. In this multimethod study, a retrospective chart review found a notable difference between the rate of HPV vaccinations and other age-appropriate vaccinations in 177 childhood cancer survivors and in 70 patients with SCD. We then sought to describe patient and caregiver beliefs regarding HPV vaccination, through semistructured interviews with 21 patients and 48 caregivers. Interviews were analyzed with a thematic content approach to understand attitudes regarding the HPV vaccination. Qualitative interviews noted that many caregivers and adolescents had baseline misconceptions regarding the HPV vaccination in general and in context with their chronic illness. It was found that a strong recommendation from a trusted subspecialty provider would create reassurance about vaccination and reduce misconceptions and concerns about side effects in the context of a chronic illness. Counseling from subspecialists could have a strong impact on understanding the HPV vaccine in the context of chronic illness. This would likely help overcome many of the barriers to vaccination that are encountered by patients with SCD or oncology survivors., Competing Interests: G.D.Z. has served as a consultant and external advisory board member for Merck regarding HPV vaccination, an external advisory board member for Moderna regarding COVID-19 vaccination, and as an external advisory board member for Pfizer regarding meningococcal vaccination. He has also received investigator-initiated research funding from Merck, administered through Indiana University. M.A.O.’s spouse is an employee of Eli Lilly Inc. The remaining authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)