Fanconi anemia (FA) is a rare genetic disorder associated with predisposition to head and neck and gynecological squamous cell cancers. In the general population, these cancers are commonly linked to human papillomavirus (HPV) infection. Antibodies to natural HPV infection and HPV vaccination were evaluated in 63 individuals with FA while considering host immune factors. Approximately 30% of reportedly unvaccinated participants were seropositive (HPV6-38%, HPV11-25%, HPV16-26%, and HPV18-26%). Seropositivity was significantly associated with having had sex regardless of age (p=.007). Most participants showed seropositivity after HPV vaccination (HPV6-100%, HPV11-100%, HPV16-100% and HPV18-92%). Interestingly, titers for all 4 subtypes were significantly lower in the post-hematopoietic stem cell transplant (HSCT) participants compared to those who received the vaccine, but had not undergone HSCT (HPV6-p=.030, HPV11-p=.003, HPV16-p=.018, HPV18-p=<.001). It is unclear if these titers sufficiently protect from new infection since protective serologic cut offs have not yet been defined for the HPV vaccine. Individual immune functions were not associated with HPV seropositivity, however, underlying heterogeneous immune deficiency may explain higher rates of seropositivity in our younger unvaccinated participants (age 4-13 years). To better measure the efficacy of HPV vaccination in those with FA and other immune-compromised or cancer-prone disorders, future well-controlled vaccine studies are required.