Abstract Opioid withdrawal is a regular occurrence among people who use illegal opioids involving acute physical and psychological pain with potentially serious health consequences, including overdose. At the same time, withdrawal is increasingly seen as an important juncture during which people who use illicit opioids may be more receptive to treatment initiation, particularly medication for the treatment of opioid use disorder (MOUD), which typically provides remediation from withdrawal. Yet, several studies have also indicated that at least some people receiving MOUD treatment still regularly experience withdrawal. The reasons for this have not yet been explored systematically. Nor is there a general empirical understanding of how these withdrawal experiences in the context of MOUD may represent a barrier to treatment or treatment adherence, or how they may differ between populations not engaged in treatment and those engaged in methadone and buprenorphine maintenance. This mixed-method supplementary study will combine qualitative insights from participants who experience regular and/or severe withdrawal in a longitudinal interview schedule with quantitative survey analysis of the parent grant’s cohort study to examine a number of hypotheses related to the associations between withdrawal, treatment, and risk of overdose. It aims to provide an empirical understanding of how withdrawal impacts people who use illegal opioids’ treatment choices over time as well as how withdrawal experiences in the context of MOUD may represent a barrier to treatment or treatment adherence. Evaluating the withdrawal experiences of people in different treatment modalities, as well as those not currently in MOUD, and assessing their impact on treatment decisions is essential to efforts to strengthen and refine existing MOUD treatment protocols and to design tailored interventions to engage opioid users that account for their experiences with opioid withdrawal. Moreover, since MOUD is recognized as among the most effective strategies for reducing rates of overdose and transmission of blood-borne viruses like HIV and HCV, improving uptake and retention in MOUD programs can significantly improve the healthcare outcomes of people with opioid use disorder.