PROJECT SUMMARY/ABSTRACT Sexual minority (SM, i.e., people who are not heterosexual) and gender minority (GM, i.e., people who have a gender that is discordant from the sex they were assigned at birth, as opposed to cisgender people who have a gender that is concordant with the sex they were assigned at birth) people (collectively abbreviated as SGM) are at greater risk for health disparities including very high rates of substance use. Within studies on substance use, GM people are largely unrepresented as GM status is rarely measured or reported. The primary explanation for the higher rates of substance use and health problems among SGM people is minority stress, which confers an additional stress burden on SGM people including experiences of discrimination, expectations of discrimination, concealment of one’s identity, and internalization of social stigma. Biological changes can occur in response to both minority stress and substance use, including activation of inflammatory pathways. Understanding biological correlates of substance use and minority stress may help us to develop better ways to identify and treat substance use disorders and to understand the downstream health outcomes of SGM people. This study will leverage the All of Us Research Program, a national study aiming to collect data from 1 million people within the United States, with strong representation of SGM participants. We will examine differences in substance use between SGM subgroups, examine relationships between minority stress and substance use patterns, and identify how substance use, minority stress, and HIV status are related to C-reactive protein (a marker of inflammation). This study will help us to better understand substance use among SGM people and inform how minority stress, substance use, and HIV may interact to alter inflammatory pathways. This study will also inform the development of biomarkers for substance use to improve substance use treatment and prevention.