Objective: To disentangle the impact of adherence from that of injecting drug status and depressive syndrome on HIV clinical progression in a cohort of highly active anti-retroviral therapy (HAART)-treated HIV patients infected through drug use. Design: MANIF 2000 is a French cohort of HIV-infected drug users with scheduled medical visits every 6 months. Only patients enrolled in the MANIF 2000 cohort who had a CD4 cell count >200 cells/µl at HAART initiation were selected. The follow-up period included all post-HAART initiation visits. Methods: HIV clinical progression was defined as either AIDS-related death or reaching a CD4 level <200 cells/µl. Adherence was assessed using a self-administered questionnaire and a structured face-to-face interview. Depressive symptoms were evaluated by a Center for Epidemiologic Studies Depression Scale (CES-D) score at each visit. Cox proportional hazards model was used to calculate crude and adjusted relative hazards and 95% confidence intervals and thus identify independent predictors of clinical progression. Results: Of the 305 HAART-treated patients in the cohort, 243 had CD4 cell count >200 cells/µl at HAART initiation. At the first visit after HAART initiation, median CD4 cell count was 466 cells/µl and 45% had undetectable viral load. Injecting drug users accounted for 17% of the study group. Over the follow-up period, 32 patients experienced HIV clinical progression. Probable depression was encountered in 46% of patients and non-adherence in 31% of the sample. After adjustment on baseline CD4 cell count, predictors of clinical progression were: having a higher level of cumulative non-adherence over the follow-up period [HR (95% CI)=1.2 (1.1–1.3) per 10% increase] and having a high score of depressive symptoms following HAART initiation [HR (95% CI)=5.3 (2.21–3.0)]. Conclusions: Although depressive syndrome is known to influence non-adherence behaviours that are amongst the major reasons for clinical progression, it is also a predictor of clinical progression in HIV-infected intravenous drug users on HAART, independently of non-adherence behaviours. HIV care providers should be more sensitive to depressive symptoms in order to detect them early and supply HIV patients with specific care. Further research is needed to determine whether treating depressive symptoms may improve adherence and thus delay disease progression and mortality.