People with HIV (PWH) in underserved racial/ethnic and marginalized populations (UREMP) carry a disproportionate burden of health disparities related to substance use and HIV. The goal of this study is to elucidate and address disparities experienced by UREMP in substance use patterns, substance use treatment outcomes and HIV-related outcomes including the contribution of social, cultural, structural, and other factors. We focus on underserved racial/ethnic populations as well as other marginalized groups such as those who are transgender, have unstable housing, or were recently incarcerated. We will 1. Determine methamphetamine, cocaine and opioid-related behaviors, risk factors, and treatment outcomes to better understand health disparities among UREMP and better tailor future intervention/treatment and prevention approaches. We will examine differences in drug-related behaviors including types, frequency, severity of use, mode of administration, polydrug use, overdoses, Naloxone access, and substance use treatment access and outcomes. We will determine the role of demographic, behavioral, psychosocial and clinical factors, and incorporate additional structural/social measures such as of racial/ethnic identity, stigma/discrimination, and other domains based on recommendations from community partners, end-users, and critical thought partners to determine risk factors for differences in drug use patterns and substance use treatment outcomes. 2. Determine the role of methamphetamine, cocaine and opioid use in HIV-related outcome disparities among UREMP. We will examine longitudinal relationships between drug use, social, cultural, and structural factors, and HIV care cascade steps such as engagement in care, viral suppression and health-related quality of life. We will determine the impact of drug use and social, structural, and other factors on age-related comorbidities, such as diabetes, frailty, myocardial infarction and chronic kidney disease among UREMP. We leverage the large well-characterized racially/ethnically, gender, and sexual orientation-diverse cohort of PWH with comprehensive clinical data in the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort. The CNICS patient reported outcomes assessment captures detailed drug use patterns, psychosocial, behavioral and other factors such as social support and racial stigma/discrimination and facilitates capturing multiple dimensions of identity. CNICS geocoding and carefully adjudicated outcomes facilitates including structural factors and evaluation of HIV-related comorbidities. CNICS data and our team bring a breadth and depth of resources, responding to RFA-DA-23-061 by generating new knowledge about substance use-related disparities among PWH from UREMP and the impact of social, structural, and cultural factors. This study will inform future research and assist end-users within our community partnerships in tailoring future substance use treatment programs to t...