The introduction of potent anti-retroviral treatment (ART) has transformed HIV disease into a chronic condition with the prospect, for the patient, of strict adherence to effective but life-long treatments. Within this framework, a major issue that can negatively affect adherence is the side-effects of the treatment. To date, studies documenting how individuals HIV-infected through drug injection (IDUs) experience ART-related side effects are sparse. Longitudinal data collected from the APROCO-COPILOTE cohort have been used to compare the experience of ART-related side-effects who have been HIV-infected via injecting drug use and non-IDU patients. A 20-item list was used to collect self-reported side-effects over a 7-year follow up period. Of 922 patients, 15% were IDUs. At any given visit, IDUs reported a significantly higher number of side-effects and had approximately twice the risk of reporting any side effect than non-IDUs. Most commonly reported side-effects were dry skin, fatigue, vomiting, bone troubles, insomnia. After adjustment for social conditions, depressive symptoms, use of sleeping pills and time since HIV diagnosis, IDUs reported experiencing significantly more side-effects than non-IDUs. Whether or not this is related to sensitivity to pain or to other comorbidities is difficult to establish. Further research is needed to understand how substitution treatment can mediate the relationship between exposure to opioids and side-effects. Providing appropriate care to reduce side-effects, thereby increasing adherence to ART in this population, remains a major challenge especially in those countries scaling up ART. Incorporating symptom management and improving access to analgesic medications within a model of comprehensive care for HIV-infected IDUs, could reduce the impact of drug-related and HIV-related harms and induce better long-term treatment outcomes and quality of life.