People living with HIV with a history of drug use face additional psychosocial challenges that could compromise their adherence to antiretroviral therapy (ART). This study examined ART treatment adherence and adherence self-efficacy among people living with HIV with a history of drug use in Vietnam. We used cross-sectional baseline data collected between October 2014 and February 2015 from a randomized controlled trial in Vietnam. Of the 900 persons with a history of drug use in the trial, a sample of 109 people living with HIV currently on ART were included in the study. The vast majority (92%) of the participants reported not missing any medications in the past 30 days. Multiple regression results indicated that social support was positively associated with adherence self-efficacy (β = 0.420, P < 0.001) and general adherence to ART (β = 0.201, P = 0.0368). General adherence to ART was negatively associated with depressive symptoms (β = -0.188, P = 0.046) and current heroin use (β = -0.196, P = 0.042). These findings underscore the importance of addressing mental health and social challenges facing people living with HIV with a history of drug use to promote ART treatment adherence. Clinical management of HIV should identify and address concurrent substance use behaviors to maximize adherence and treatment outcomes.