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Introduction: Successful engagement with medication treatment for opioid use disorder is an important focus in reducing mortality associated with the opioid crisis. Mortality remains at unacceptably high levels, pointing to a need for improved understanding of factors that affect medication for opioid use disorder outcomes. This study aims to understand how barriers co-occur and interact to interfere with outcomes in methadone treatment for a low-income, underserved patient population with opioid use disorder., Methods: This study was conducted at a community-based drug treatment center that serves a predominately low-income, racially diverse population. Guided by the social-ecological framework, we analyzed semi-structured interviews and focus groups with patients and providers working in opioid use disorder care and recovery across Baltimore City (N = 32) to assess factors that influence methadone treatment outcomes, and how barriers co-occur and interact to worsen treatment outcomes. The study used patient-centered definitions to describe successful treatment outcomes., Results: Barriers described by both patients and providers fit into several broad levels: individual, interpersonal, institutional, community, and stigma. Participants described co-occurrence of many barriers. Further, the study identified potential interactive effects, such that interrelated barriers were seen as fueling one another and having a deleterious effect on treatment outcomes. Specifically, interrelationships between barriers were described for 1) unstable housing with social influences and mental health factors; 2) transportation with poor physical health and other competing responsibilities; 3) treatment program policies and schedule with competing responsibilities; and 4) stigma with poor physical and mental health., Conclusions: Understanding barriers to successful medication for opioid use disorder outcomes and considering their co-occurrence may help to identify and promote interventions to mitigate their impact. This work is intended to guide future research to adapt conceptual frameworks for understanding psychosocial and structural barriers affecting opioid use disorder treatment and ultimately intervention efforts to improve treatment outcomes., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)