Abstract We propose a multiphase study focused on American Indian, socioeconomically disadvantaged, and underserved rural populations of youth. Our goal is the primary prevention of leading risk factors (i.e., mental health, substance use) for causes of premature mortality for which AI/AN populations are at increased risk (e.g., suicide, motor vehicle crashes, drug overdose). With the support of the administrative supplement, we will enhance and strengthen our multilevel community opioid preventive intervention funded by NIDA as part of the HEAL Prevention Initiative. The UH3 parent trial is a cluster randomized trial of 20 rural high schools in underserved small towns in or near the Cherokee Nation Reservation with over 900 enrolled 15- to 16-year-old American Indian (56%) and other youth. Family, school and community prevention strategies will be enhanced to address the emerging risk of the proliferation of dispensaries and marketing of cannabis since Oklahoma legalized medical marijuana in 2018. Study aims will address the following research questions. How many cannabis advertisements are visible near high schools in the Cherokee Nation Reservation? Does the quantity of cannabis advertisements differ by the racial and socioeconomic composition of schools? Do cannabis advertisements near high schools in the Cherokee Nation Reservation target or appeal to youth and American Indian people? Do preventive intervention components designed to counter cannabis marketing contribute to increased perceived risks, increased social disapproval, reduced perceived access, or reduced current marijuana use? During the year of the supplement, we will (1) document cannabis advertisements near high schools in the Cherokee Nation Reservation, (2) conduct content analysis by community-based youth coders of cannabis advertisements, (3) develop enhanced preventive intervention components to address cannabis marketing exposure with media messages, Family Action Kit, and Community Action Guides. Following the year of supplemental activities, we implement the enhanced intervention components during the final year of the intervention trial and conduct outcome analyses, which will include marijuana use as well as perceived risk, norms, and access. Study aims are relevant and responsive to local conditions and needs within the Cherokee Nation Reservation. Results of all three phases of research will provide important contributions to the field about cannabis marketing, as well as effectiveness of culturally tailored marijuana prevention strategies for adolescents in the Cherokee Nation.