ABSTRACT: Objective:Prescription opioid misuse has led to a new cohort of opioid use disorder (OUD) patients who were introduced to opioids through a legitimate prescription. This change has caused a shift in the demographic profile of OUD patients from predominantly young men to middle age and older people. The management of OUD includes medication-assisted treatment (MAT), which produces varying rates of treatment response. In this study, we will examine whether the source of first opioid use has an effect on treatment outcomes in OUD. Using a systematic review of the literature, we will investigate the association between source of first opioid introduction and treatment outcomes defined as continuing illicit opioid use and poly-substance use while in MAT. Methods:Medline, EMBASE, CINHAL, and PsycInfo were searched from inception to December 31st, 2019 inclusive using a comprehensive search strategy. Five pairs of reviewers conducted screening and data extraction independently in duplicate. The review is conducted and reported according to the PRISMA guidelines. A random-effects model was used for meta analyses assuming heterogeneity among the included studies. Results:The initial search results in 27,345 articles that were screened, and five observational studies were included in the qualitative and quantitative analyses. Our results found that those who were introduced to opioids through a legitimate prescription were significantly less likely to have illicit opioid use (0.70, 95% CI 0.50, 0.99) while on MAT. They were also less likely to use cannabis (0.54, 95% CI 0.32, 0.89), alcohol (0.75, 95% CI 0.59, 0.95), cocaine (0.50, 95% CI 0.29, 0.85), and injection drug use (0.25, 95% CI 0.14, 0.43) than those introduced to opioids through recreational means. Conclusion:This study shows that the first exposure to opioids, whether through a prescription or recreationally, influences prognosis and treatment outcomes of opioid use disorder. Although the increased pattern of prescribing opioids may have led to increased OUD in a new cohort of patients, these patients are less likely to continue to use illicit drugs and have a different prognostic and clinical profile that requires a tailored approach to treatment. Systematic Review Registration:PROSPERO CRD42017058143.