In the era of highly effective anti-retroviral therapy (ART), data show a significant difference in treatment outcomes between injecting drug users (IDUs) and non-IDUs. Factors that may contribute to suboptimal treatment outcomes in IDUs include delayed access to ART, competing comorbid diseases, psychosocial barriers and poor long-term adherence to ART. This review describes and compares several studies on adherence to ART and its correlates in HIV-infected individuals in general, then IDUs and finally those IDUs on opioid substitution treatment (OST). It highlights how ongoing drug use or OST can modify the pattern of these correlates. The aim is to extend all the experience acquired from these studies in order to optimise both access to care and adherence in those countries where HIV infection is mainly driven by IDUs and where ART and OST are only starting to be scaled up. The role of OST in fostering access to care and adherence to ART together with the promising results achieved to date using modified directly observed therapy (DOT) programs for patients taking methadone, allow us to emphasize the efficacy of a comprehensive care model which integrates substance dependence treatment, psychiatric treatment, social services, and medical treatment. The review concludes by suggesting areas of future research targeted at improving the understanding of both the role of perceived toxicity and patient-provider relationship for patients on ART and OST.