["Sociology of Health & Illness, Volume 43, Issue 5, Page 1286-1300, June 2021. ", "\nAbstract\nIn randomised controlled trials (RCTs), ‘therapeutic optimism’ describes a participant's belief they will benefit from the study treatment, despite the express goal of RCTs to test unknown aspects of interventions. Harbouring such expectations may interfere with RCT participation experiences, particularly among marginalised populations, such as people with substance use disorders (PSUD) who may experience social and structural barriers to participation that also increase their vulnerability to therapeutic optimism. However, little research explores therapeutic optimism within substance use trials. Thus, we conducted a nested qualitative study within an RCT testing a treatment for alcohol and opioid use disorders in HIV clinics. Using interviews with 22 participants in Vancouver, Canada, analysis revealed themes relevant to therapeutic optimism, that were specifically linked to intrinsic (e.g. health‐related) or extrinsic motivations (e.g. stipend). First, compared to extrinsically motivated participants, intrinsically motivated participants held high expectations for the trial and attributed greater agency to the study medication. Second, intrinsically motivated participants expressing therapeutic optimism anticipated marked changes in their lives from the study/medication. Finally, some participants predicted the treatment would solve substance‐related issues in their communities. These findings highlight the interplay between therapeutic optimism and complex interpretations of RCT objectives among PSUD.\n"]