PROJECT SUMMARY The novel coronavirus (COVID-19) has exacerbated health disparities throughout the United States (US) and impacted American Indian/Alaska Native (AI/AN) populations in significant ways. Arizona has the third largest population of AI/AN in the US (over 350,000) and is home to 22 federally recognized sovereign Native nations. Compared with Whites, AI/AN in Arizona have a significantly higher prevalence of health risk factors that increase their susceptibility to COVID-19. AI/AN represent approximately 4.6% of the state’s population, yet account for 19% of COVID-19 deaths where race and ethnicity of victims is reported. The long-term goal of this study is to conduct community-engaged research and outreach to increase COVID-19 awareness and education among AI/AN communities in Arizona disproportionately affected by COVID-19 and to reduce misinformation and mistrust. The goal of this Administrative Supplement is to establish effective, culturally appropriate strategies to enhance participation of AI/AN communities in prevention and treatment of COVID- 19, including vaccine trials and future vaccine uptake. This work will be guided by a community engagement framework, which emphasizes equitable participation between scientists and community members in all phases of the research. In partnership with AI/AN communities in the catchment area of the parent U54 RCMI: The Southwest Health Equity Research Collaborative (SHERC), we aim to: 1) Assess awareness, knowledge, experiences, concerns, attitudes, and needs regarding COVID-19 vaccine trials and vaccination uptake among AI/AN communities in Arizona; 2) Develop and adapt culturally-appropriate educational materials and strategies designed to increase awareness of COVID-19 vaccine trials, decrease misinformation, and increase medical trust; and 3) Implement the educational session and evaluate the impact of educational materials and strategies on enhanced awareness, trust, self-efficacy, and willingness and intent to participate in COVID-19 vaccine trials and future vaccines. There is an urgent need to better address the concerns of AI/AN communities at this critical juncture of the COVID-19 pandemic in Arizona. Knowledge derived from this study has the potential to build awareness about COVID-19 vaccine trials and enhance participation among AI/ANs in the trials and future vaccine uptake. The unique geographical and cultural setting of SHERC, combined with the experience and expertise of this interdisciplinary team of investigators, well-positions the proposed study for success.