PROJECT SUMMARY/ABSTRACT Mental health and substance misuse pose some of the greatest risks to the health and wellbeing of American Indian and Alaska Native (AI/AN) communities and result in intergenerational morbidity and mortality. These risks are the legacy of historical trauma, ongoing discrimination, and chronic underfunding of mental health and substance use care, resulting in massive care and treatment gaps. Simultaneously, many AI/AN communities emphasize a holistic view of wellbeing centered around family and community, and prefer upstream preventative and family-based interventions with potential to disrupt intergenerational cycles of trauma and adversity. Our team of Indigenous and allied researchers has worked closely with participating communities to design and pilot the Family Spirit Strengths (FSS) intervention, designed to provide transdiagnostic skills- based preventive strategies to mothers and primary caregivers at elevated risk for mental health and substance use disorders. We propose a Hybrid Type I Effectiveness-Implementation design with the primary goal of testing FSS effectiveness at reducing symptoms of depression, anxiety, and substance use, among N = 188 primary caregivers across three diverse Tribal settings and contexts. Participants will be randomized to receive FSS or a beneficial control, which is an evidence-based nutritional support program called Family Spirit Nurture. Primary outcomes will be measured at 6 months post-enrollment. We will also seek to characterize heterogeneity in and mechanisms of FSS effects by exploring moderators and mediators, respectively, guided by both Western and Indigenous theories of action. As part of our Hybrid approach, we will estimate FSS costs, cost-effectiveness, and budget impact. Finally, we will undertake a process with National stakeholders to understand barriers to and facilitators of FSS implementation across the country, including co-design of implementation strategies to support FSS at scale across diverse AI/AN communities. This study is responsive to Program Announcement PAR-20-238 and focuses on key areas of interest including the testing of evidence- based practices in community settings (MH-22-170) and expanding perinatal mental health interventions (MH- 21-215, MH-21-270). Our overall objective is to rigorously test a secondary preventative intervention designed to be embedded in home visiting programs so that we can extend the reach of mental and behavioral health services in AI/AN communities across the country.