A mainstay treatment for opioid addiction in North America is methadone maintenance therapy (MMT) – a form of opiate agonist therapy (OAT). While efficacious for treating opioid addiction, MMT fails to address the concurrent polysubstance use that is common among opioid dependent clients. Moreover, psychosocial approaches for addressing polysubstance use during MMT are lacking. Our study's goals were to validate the use of the four-factor personality model of substance use vulnerability in MMT clients, and to demonstrate theoretically-relevant relationships of personality to concurrent substance use while receiving MMT. Respondents included 138 daily-witnessed MMT clients (65.9% male, 79.7% Caucasian), mean age (SD) 40.18 (11.56), recruited across four Canadian MMT clinics. Bayesian confirmatory factor analysis was used to establish the structural validity of the four-factor personality model of substance use vulnerability (operationalized with the Substance Use Risk Profile Scale SURPS) in MMT clients. SURPS personality scores were then used as predictors for specific forms of recent (past 30-day) substance use. Using a latent hierarchal model, hopelessness was associated with recent opioid use; anxiety sensitivity with recent tranquilizer use; and sensation seeking with recent alcohol, cannabis, and stimulant use. Personality is associated with substance use patterns and may be an appropriate target for intervention for those undergoing MMT to reduce opioid use, and potentially dangerous concurrent use of other drugs, while receiving methadone. Display omitted •Personality is associated with the use of specific substances among MMT clients in the past-30 days.•Hopelessness was associated with opioid use.•Anxiety-sensitivity was associated with tranquilizer use.•Sensation-seeking was associated with alcohol, cannabis and stimulant use.