Childhood mistreatment (CM)/victimization, posttraumatic stress disorder (PTSD), and lifetime substance-use disorders (LT-SUD) are major behavioral health concerns. Their associations were established in mainstream populations but remain under-investigated in Latinx Americans. This study aimed to model the mediating effect of PTSD in the link between CM and LT-SUD among Latinx Americans. Using a nationally representative sample (N = 2,554) from the National Latinx and Asian American Study, three path models were performed for the whole-group, U.S.-born, and foreign-born Latinx (aged 18 or over), controlling for known predictors for Latinx' mental health. Latinx reported high rates of childhood physical (32%) and sexual (11.8%) abuse. Latinx subgroups significantly varied in educational attainment, LT-SUD, income, English proficiency, and self-reported discrimination. A fully constrained multiple group path analysis demonstrated direct effects of childhood physical mistreatment (CPM) and childhood sexual mistreatment to lifetime PTSD; PTSD significantly mediated the relationship between CPM with LT-SUD. No significant differences in path coefficients were observed among the Mexican, Cuban, and Puerto Rican subgroups. Findings suggest that CPM may contribute to using substance to avoid physical and emotional pain, which lends support for the self-medication hypothesis. Latinx who were traumatized by both physical and sexual abuse are more likely to use substances as a negative coping strategy. The study underscores the need for assessing the role of substance use as a coping mechanism for Latinx individuals who have experienced childhood traumatic victimization. (PsycInfo Database Record (c) 2024 APA, all rights reserved).