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Background: Comparative studies of the naturalistic course of patients of opioid dependence on naltrexone and buprenorphine are likely to be helpful for clinical decision-making. The article aimed to report on the three-months naturalistic outcomes of patients discharged on naltrexone or buprenorphine from the same center. Methods: Patients with opioid dependence who were discharged on either naltrexone (n = 86) or buprenorphine (n = 30) were followed up for three months for retention in treatment. The patients were also followed up telephonically, and the Maudsley Addiction Profile was applied. Results: The days of retention in treatment were significantly higher in the buprenorphine group (69.5 versus 48.7 days, P = 0.009). Heroin use, pharmaceutical opioid use, injection drug use, involvement in illegal activity, and percentage of contact days in conflict with friends in the last 30 days reduced over three months in both the groups, while the physical and psychological quality of life improved in both the groups. Additionally, in the naltrexone group, smoked tobacco use, cannabis use, and percentage of contact days in conflict with family within the last 30 days reduced at three months compared to baseline. Conclusion: With the possible limitations of choice of medication-assisted treatment for opioid dependence being determined by the patient, and prescribing related factors and sample size constraints, the study suggests that retention outcomes may vary between naltrexone and buprenorphine, though both medications may improve several patient-related parameters. However, a true head-to-head comparison of the outcomes of buprenorphine and naltrexone in a naturalistic setting may be difficult. [ABSTRACT FROM AUTHOR]