Lurie Children’s Hospital (LCH) and Haymarket Center will implement Connect For Youth (C4Y), a citywide, trauma-informed, integrated substance misuse and HIV prevention strategy for high-risk racial/ethnic minority youth ages 16–25 in Chicago (Cook County, IL). C4Y concentrates on low-income, under-resourced communities where youth experience high levels of trauma—stemming from crime, gun violence, and domestic instability—that contribute to unsafe behaviors. C4Y will partner with the Youth Substance Use Prevention Coalition (SUPC), City agencies (e.g. Chicago Public Schools, Chicago Public Library, and Chicago Park District); community-based organizations; and SUPC’s Youth Advisory Committee to 1) Increase understanding of the intersection of HIV and substance misuse and the importance of prevention/treatment among minority youth; 2) Increase access to comprehensive, youth-friendly integrated screening and testing for HIV, viral Hepatitis, and substance use; 3) Increase linkage to, engagement in, and retention in care for low-income and high-risk racial/ethnic minority youth; and 4) Increase capacity of other adolescent-health providers to address the intersection of trauma, youth substance use, and HIV to raise awareness of the HIV Care Continuum with minority youth. C4Y will implement youth-specific HIV/substance misuse prevention campaigns (in English and Spanish) online and via print materials, reaching at least 10,000 youth in the target population per year (reduced by 33% in year 1 to allow for project start-up)/46,700 over five years. The program will deliver trauma-informed, integrated HIV/substance misuse prevention education in public schools, other community youth venues, and via youth-focused outreach events, serving at least 100 unduplicated racial/ethnic minority youth per year (reduced by 33% in year 1)/467 over five years. C4Y will also deliver prevention education in conjunction with integrated HIV/hepatitis/substance use screening, counseling, testing, and referrals (CTR). C4Y will partner with community organizations and leverage LCH’s Mobile Health Unit to implement, at minimum, 36 CTR events per year (reduced by 33% in year 1)/168 events over five years in medically under-resourced communities, serving 100 unduplicated racial/ethnic minority youth per year (reduced by 33% in year 1)/467 unduplicated over five years. C4Y will also introduce new Navigation Services to overcome persistent structural and socioeconomic barriers to care by expediting participants’ access to treatment; offering ongoing counseling, monitoring, and assessment; and supporting retention in treatment. C4Y’s Lead Navigator will provide enhanced services to at least 65 unduplicated participants per year (reduced by 33% in year 1)/304 unduplicated participants over five years who 1) screen as moderate- or high-risk for HIV and/or substance misuse; 2) test positive for Hepatitis and/or HIV; or 3) have active substance-use disorders. Lastly, LCH’s clinicians and project staff will partner with adolescent-health providers in the targeted communities to train 50 unduplicated clinicians per year/250 unduplicated over five years in the HIV Care Continuum and the intersection of trauma, substance use/misuse, and HIV, increasing local capacity to provide holistic care to the target population.