Abstract Background: Although the incidence of cervical cancer in the US has declined, the incidences of other HPV-associated cancers are on the rise. HPV vaccination is an important primary prevention strategy for reducing the burden of HPV-associated cancers. In South Florida (population over 6 million), the percentage of adolescents aged 13-15 years who completed the recommended HPV vaccine series is 54%, which lags significantly behind the Healthy People 2030 target of 80%. In addition, vaccination disparities exist in South Florida by races/ethnicities and sexes, with non-Hispanic black males having the lowest rate at 27%. To address HPV cancer disparities, we performed a geospatial analysis on the incidence of HPV-associated cancers by sex and races/ethnicity to identify communities in South Florida with high incidence of HPV-associated cancer to target interventions that may improve HPV-vaccine uptake via community outreach and engagement. Methods: The average annual (2010-2019) incidence of HPV-associated cancers in women (cervical, oropharyngeal, vulva, vaginal, and anal) and men (oropharyngeal, penile, and anal) were calculated for Hispanics, Non-Hispanic Whites (NHWs) and Non-Hispanic Blacks (NHB) at the census tract level across South Florida using data from the Florida Cancer Data System (FCDS), the state incident cancer registry. Geospatial hot spot analyses were used to identify clusters of census tracts with high HPV cancer incidence by sex and race/ethnicity. Socioeconomic and cervical screening data of the hot spots were analyzed to identify other neighborhood risk conditions that may be associated with high HPV cancer risk. Results: For Hispanics and NHBs in South Florida, census tract hot spots for male and female HPV cancers appear to overlap in low-income neighborhoods; however, hot spots for NHW males are mostly in medium to higher income areas and do not overlap with hot spots observed for NHW females, likely given that NHW females generally report higher cervical screening rates. Conclusion: There is a positive association between male and female HPV cancer incidence in Hispanic and NHB communities of South Florida, justifying the need for increased HPV vaccination and screening programs in these neighborhoods. While increasing cervical screening rate in the hot spot neighborhoods is urgent for cervical cancer control, increasing gender-neutral HPV vaccination uptake in these communities will not only reduce the incidences of male HPV cancers but also help to accelerate cervical cancer elimination by reducing HPV infection. Citation Format: Ming Lee, Sara Parrott, Rebecca Kaiser, Ridhi Vyas, Danielle Gabuzda, Arianna Vazquez, Daniela Flores Quetant, Nancy Elliott, Valerie Bethel, Amanda Rivera, Brandon Mahal, Raymond Balise, Elizabeth Franzmann, Erin Kobetz. Identifying neighborhood hot spots of HPV-associated cancers for targeted interventions of HPV vaccination uptake in underserved communities of South Florida [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4805.