PROJECT SUMMARY Indigenous Peoples have the highest rate of prescription opioid misuse of any sociodemographic group in the United States (US). Increasing rates of opioid misuse have led to increased prevalence of injection drug use (IDU) and concomitant overdose and infectious disease morbidity and mortality. Infectious disease inequities are driven in part by inadequate access to sterile injection equipment. IDU-associated harms are one of many drivers of Indigenous Peoples having the lowest life expectancy of all racial and ethnic groups. Despite sustained health inequities among Indigenous Peoples, very few Federally recognized tribes in the US have implemented syringe services programs (SSPs). This scarcity is driven in part by the fact that SSPs – which reflect harm reduction and, often, allopathic “western” approaches to health and well-being – must be integrated with traditional Indigenous approaches for healing. While these three approaches are not incompatible, their integration can be challenging. Understanding factors that facilitated the successful implementation of Indigenous-centered SSPs that integrate harm reduction, allopathic “western,” and traditional Indigenous approaches warrants exploration since these programs are essential for mitigating IDU-associated harms. We will conduct community-based participatory research with Indigenous communities that successfully implemented SSPs that integrate multiple approaches to health and well-being. Through this Project, we will identify the roles of cultural factors, community contexts, and policy during the implementation of SSPs that integrate multiple approaches (i.e., harm reduction, allopathic “western,” and traditional Indigenous) to health and well-being in three diverse Indigenous communities through key informant interviews with persons who played a role during implementation (Aim 1). We will also determine the contexts and mechanisms by which cultural, social, and structural factors affect attitudes and beliefs about the utilization of SSPs that integrate multiple approaches among Indigenous-SSP clients and Indigenous non-clients (Aim 2). Finally, we will examine how patterns of knowledge and attitudes about multiple approaches to health and well-being and SSPs that integrate them are associated with sociocultural factors (e.g., cultural identification, stigma) through audience segmentation research among Indigenous-serving members of the public health and healthcare workforce (Aim 3). The results of this Project will culminate in a robust evidence base for reversing the inertia of the status quo and eliminating substance use harms in Indigenous communities. This Project is directly aligned with the goals of the NIDA Racial Equity Initiative given that Indigenous Peoples have persistent health inequities. This Project is highly innovative as it will be the first in the US to comprehensively examine SSP implementation processes in Indigenous communities.