Abstract North Carolina (NC) is home to the largest American Indian population in the Eastern United States (approximately 300,000 residents, about 2.8% of the total NC population), represented by eight state and federally recognized tribes (Eastern Band of Cherokee Indians, Sappony, Occaneechi Band of Saponi Nation, Meherrin, Haliwa Saponi, Coharie, Lumbee, Waccamaw Siouan) and four urban Indian organizations (Metrolina Native American Association, Guilford Native American Association, Triangle Native American Society, Cumberland County Association for Indian People). This population experiences significant health disparities largely related to adverse social determinants of health and limited access to health care. With regards to cancer, disparities exist for incidence and mortality for certain cancer, although there are limited data available with regards to cancer screening stage at diagnosis, treatment and survivorship. Furthermore, evidence suggests that racial misclassification contributes to a significant underestimation of the true cancer incidence and mortality in this population. To address the cancer care needs of NC American Indians, a unique collaboration was established in 2021 among the leadership of the Community Outreach and Engagement programs at the three NCI-designated Comprehensive Cancer Centers in North Carolina (Duke Cancer Institute, University of North Carolina Lineberger Cancer Center, Wake Forest Baptist Comprehensive Cancer Center). The collaboration, entitled, The Southeastern American Indian Cancer Health Equity Partnership (SAICEP), has as its mission to "understand and address the cancer-related health needs of American Indian communities in our catchment areas and beyond." SAICEP includes: (1) a quarterly speakers' series, featuring nationally recognized experts in the area of American Indian cancer research and care; (2) educational outreach and engagement activities at tribal and state cultural events; and, (3) cutting-edge culturally respectful research to understand and address cancer disparities at the tribal and state level. Partnerships have been established with tribal leaders across the state as well as researchers at the University of North Carolina at Pembroke in the traditional homeland of the Lumbee tribe (the largest tribe in the state). Future endeavors will include partnerships with tribes in other states in our catchment areas (Virginia, South Carolina). Citation Format: Ronny A. Bell, Tomi Akinyemiju, Stephanie B. Wheeler. Understanding and addressing cancer disparities among American Indians in North Carolina: The Southeastern cancer health equity partnership [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C112.