Abstract PURPOSE: Glioma is the most common type of primary malignant brain tumor, and incidence is 25% lower in U.S. Hispanics than White non-Hispanics. Though often pooled in epidemiological analyses, the U.S. Hispanic population is very diverse, and registry-based analyses may mask incidence and survival differences associated with geographic/ancestral origins. METHODS: County-level glioma incidence data in U.S. Hispanics from 2000-2017 were retrieved from the Central Brain Tumor Registry of the United States, and survival data from the CDC’s National Program of Cancer Registries was obtained for 2001-2017. American Community Survey data were used to determine county-level proportion of the Hispanic population of Mexican/Central-American origin and of Caribbean origin (Puerto Rican, Cuban, Dominican). State-level estimates of European and African admixture in Hispanics were obtained from published 23andMe data. Incidence rate ratios (IRRs) quantified the glioma incidence differences across groups. County-level incidence was modeled using linear regression to control for potential confounding factors (e.g., county size, median socioeconomic status), and Cox proportional hazards models were used to assess associations between individual-level survival, county-level origin percentages, and state-level admixture. RESULTS: Compared to Hispanics living in predominantly Caribbean-origin counties, Hispanics from predominantly Mexican/Central-American-origin counties had lower age-adjusted risks of glioma (IRR=0.83; P<0.0001), glioblastoma (IRR=0.86; P<0.0001), diffuse/anaplastic astrocytoma (IRR=0.78; P<0.0001), oligodendroglioma (IRR=0.82; P<0.0001), ependymoma (IRR=0.88; P=0.012), and pilocytic astrocytoma (IRR=0.76; P<0.0001). Associations were consistent in children and adults, and using more granular geographic regions. Despite having lower glioma incidence, Hispanic glioblastoma patients from predominantly Mexican/Central-American-origin counties had poorer survival than Hispanics living in predominantly Caribbean-origin counties. Incidence and survival differences could be partially explained by state-level estimates of European and African admixture in Hispanics, with European admixture associated with higher incidence and African admixture associated with improved survival. CONCLUSIONS: Glioma incidence and outcomes differ in association with the geographic origins of the Hispanic community, with residents of predominantly Mexican/Central-American-origin counties at significantly reduced risk and those of Caribbean-origin counties at comparatively greater risk. Although typically classified as a single ethnic group in registry data, appreciating the cultural, socioeconomic, and genetic diversity of U.S. Hispanics will help advance cancer disparities research. Citation Format: Kyle M. Walsh, Corey Neff, Melissa L. Bondy, Carol Kruchko, Jason T. Huse, Christopher I. Amos, Jill S. Barnholtz-Sloan, Quinn T. Ostrom. Influence of geographic/ancestral origin on glioma incidence and outcomes in US Hispanics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 26.