Project Summary/Abstract While research on substance using youth experiencing homelessness (YEH) is increasing, there is a dearth of information regarding effective prevention interventions for these youth. This is of significant concern because studies indicate that 66% to 89% of YEH have a mental health disorder (Cauce et al., 2004) and 68% report at least one suicide attempt (Gewitz et al., 2020). In fact, suicide is the leading cause of death among YEH (Rotheram-Borus & Milburn, 2004; Yoder et al., 2010). Among those who have attempted suicide, an average of 6.2 attempts is reported, and lifetime suicidal ideation rates range from 14% to 66.5% (Yoder et al., 2010) with no clear evidence of effective interventions for YEH. This study uses general cognitive theory (Beck, 1967), complemented with concepts from two suicide specific theoretical models, to guide our intervention and conceptual change model. Our goal is to test strategies to extend delivery and uptake of a cognitive therapy intervention for YEH. Prior studies focus on service-connected youth, but research suggests that most street living YEH do not access services meant to assist them (Kelly & Caputo, 2007). We overcome prior sampling limitations through engaging service-disconnected youth in addition to service-connected youth through a local drop-in center. As such, three hundred substance using YEH with recent suicidal ideation or a recent suicide attempt will be randomly assigned to Cognitive Therapy for Suicide Prevention (CTSP) + Services as Usual (SAU) (N=150) or to SAU alone (N=150). CTSP has previously shown efficacy for YEH through a RCT pilot feasibility study (Slesnick et al., 2020; Wu et al., 2020). SAU includes outreach, advocacy and service linkage which are typical services offered by agencies serving those experiencing homelessness (Ober et al., 2012). Follow-up assessments will be conducted at 3, 6, 9 and 12-months post-baseline. It is hypothesized that youth receiving CTSP+SAU will show greater reductions in suicidal ideation (primary outcome), substance use and depressive symptoms (secondary outcomes) over time compared to SAU alone, as well as improved risk and protective factors. Theoretically-derived mediators will be tested to shed light on mechanisms associated with change, and the moderating effects of sex, race, sexual orientation and baseline service connection will be examined. In order to ease future dissemination of the intervention to agencies serving YEH, we will rigorously assess acceptability, feasibility, fidelity and cost associated with the delivery of our intervention approach using a mixed-methods approach. Ultimately, the goal of this research is to provide support for the use of a suicide prevention intervention for substance using YEH that reduces premature mortality, hospitalization, and loss of human capital and which can be easily adopted by agencies serving YEH.