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Background: The prevalence of opioid use disorder (OUD) in the United States is a major public health crisis with deadly consequences. There have been many health care policies put in place to discourage the over prescribing of opioid analgesics that contributed to the numbers of people affected by this epidemic. While prevention is a worthy effort, there will always be people suffering from opioid addiction who will need treatment. Currently, buprenorphine, methadone, and naltrexone formulations are being used to treat this condition. Both buprenorphine and methadone are opioid receptor agonists, while naltrexone is an opioid receptor antagonist. Consequently, there has been controversy surrounding the use of buprenorphine and methadone as treatment for this chronic condition. Therefore, it is important to exam the efficacy and safety profiles of these drugs as medication assisted therapies (MAT) and how they can be utilized in different clinical settings. The terms primary care and officebased setting will be used interchangeably throughout this paper, it is important to note that the only difference is that an office-based setting can also include outpatient specialty care such as psychiatry or pain management. While specialized treatment program or opioid treatment program refers to a methadone clinic. Objective: To summarize evidence regarding the efficacy of methadone maintenance therapy in the outpatient setting and its potential to improve treatment outcomes. Methods: A systematic literature review was conducted using PubMed, Medline Complete, and Google Scholar. Search terms were used to narrow down the article selection and inclusion and exclusion criteria were applied to filter out irrelevant articles. The quality of the articles was assessed using a quality assessment tool designed by the National Heart, Lung, and Blood v Institute. A total of seven articles were selected and data was systematically extracted using a tool designed in Microsoft Excel. Results: Seven studies were used in this systematic review, including: two cohort studies, three systematic reviews, one randomized intervention trial, and one secondary data analysis. Allcause mortality was improved with treatment with rates for all‐cause mortality (ACM) per 100 person‐years being 0.51 on treatment versus 1.57 off treatment, resulting in an adjusted mortality rate ratio of 3.64. Buprenorphine had lower ACM than methadone as well as lower drug-related poisoning versus methadone at treatment initiation (IRR= 0.08,95% CI = 0.01–0.48) and rest of time on treatment (IRR = 0.37, 95% CI = 0.17–0.79) however, another study found no difference in adverse events between these two therapies despite their differing safety profiles Aside from safety profiles, treatment duration (mean and median) was shorter on buprenorphine than methadone (173 and 40 versus 363 and 111, respectively). Short-term retention was higher in the primary care (PC) setting than in specialized clinics (SC) (86% in PC versus 67% in SC) (p = 0.005;95% CI)) and patients admitted to primary care had lower rates of opioid use based on overall urine toxicology (63% versus 85%). Retention in methadone treatment was better than buprenorphine (61% vs. 42%). Long-term retention at 12 months was better in PC than SC (83% vs. 50%). Patients in a primary care setting were more likely to achieve three or more consecutive weeks of abstinence than in a specialty clinic (43% versus 13% (p =0.02;95% CI)) and after 1 year (55% vs. 33% (p = 0.0023;95% CI)). Quality Health Indicators (QHI) including HIV, HBV, HCV, Syphilis, hypertension, hyperlipidemia, cervical, breast, and colorectal cancers were better in buprenorphine treatment than no treatment[(AOR) = 2.19;95% CI) = 1.18±4.04)]. Enrollment in MMT reduced street drug use and crime while improving employment outcomes vi when compared with no treatment (p = < 0.0001;95% CI) and patients experienced greater psychological well-being than those without treatment (p =0.060;95% CI) Conclusion: Buprenorphine may be a more appropriate first line agent, but methadone could be an effective alternative agent for addressing the patients that fail this therapy in the primary care setting. Additional controlled clinical trials and studies conducted in the United States are warranted to evaluate the other factors and consequences associated with methadone treatment in primary care.