People with a history of interpersonal trauma, including intimate partner violence, sexual assault, and adverse childhood experiences, are disproportionately affected by the current opioid epidemic. Interpersonal trauma has been shown to increase risk for chronic pain conditions, prescription opioid use, and opioid misuse. Stress, cognition, and affective function have been examined as potential mechanisms that may influence opioid misuse among individuals with a history of interpersonal trauma. However, no studies have examined these factors simultaneously, despite their interrelatedness.The purpose of this study was to 1) examine perceived stress, perceived cognitive function, depressive symptoms, and PTSD symptoms as potential mechanisms of opioid misuse among individuals with a history of interpersonal trauma, 2) examine the types of interpersonal trauma that are associated with opioid misuse, and 3) assess the mediating role of pain and opioid prescription.A cross-sectional, observational study design was conducted. Data were collected through a confidential self-report online survey using validated instruments (n = 230). A series of regression analyses were conducted to identify mechanistic factors and interpersonal trauma types associated with opioid misuse, opioid prescription, and pain intensity. Structural equation modeling was used to examine mediating effects of pain intensity and opioid prescription.Opioid prescription, depressive symptoms, and intimate partner violence increased the odds of reporting opioid misuse. Pain intensity and adverse childhood experiences increased the odds of opioid prescription. Higher levels of perceived stress and depressive symptoms were associated with increased pain intensity. Pain intensity emerged as a mediator of the relationship between depressive symptoms and opioid misuse.Our work shows that there are likely several pathways through which interpersonal trauma can lead to opioid misuse. Interventions aimed at improving depressive symptoms and coping with traumatizing events should be included as part of comprehensive trauma-informed pain management practices.