Substance use disorders (SUDs) have substantial healthcare and economic costs as well as accidental deaths from drug overdose. Adolescence is a critical period in which exposure to alcohol and other drugs markedly increases the risk for SUD. Early-life adversity (ELA), including interpersonal trauma and loss, family dysfunction and poverty, is highly prevalent and a well-established risk factor for SUD. Individuals with ELA have an earlier age of onset for the initiation and transition to SUD, greater severity and a more pernicious course, marked by a greater risk for relapse and poor treatment response, compared to counterparts without ELA. The neuroimmune network hypothesis postulates that ELA sensitizes the brain circuits involved in threat and reward processing via inflammation, initiating positive feedback loops between these systems. Also, inflammatory mediators engage these neural circuits, predisposing individuals to emotional dysregulation, and “self-medicating” behaviors, such as smoking and drug use. Such self-medicating behaviors in adolescence, a period of high neuronal plasticity, can exacerbate the neurotoxic effects of ELA, with a quicker transition from use to disorder. To our knowledge, this theory has not been tested empirically. Adolescent studies characterizing inflammatory processes in relation to ELA focused on non-specific systemic markers of inflammation which may lack sensitivity in young, healthy persons to detect the early signs of pathogenesis, and the mechanistic specificity to inform modifiable pathways, by which health disparities emerge during this developmental period. The proposed investigation addresses these theoretical and methodological issues in the following ways: (1) we will recruit adolescents, stratified based on ELA and oversampling the high-ELA group, without a prior history of substance misuse or SUD, to examine the probability of SUD onset over a 24-month prospective follow-up; (2) examine whether an inflammatory index