Objective: To determine the impact of depressive symptoms on mortality among HIV/AIDS patients first initiating HAART and the potential role of patient adherence as a confounder and effect modifier in this association. Methods: The study comprised HIV-positive individuals who were first prescribed HAART between August 1996 and June 2002. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale. Cox proportional hazards models were used to determine the association between depressive symptoms, adherence and all-cause mortality while controlling for several baseline confounding factors. Results: A total of 563 participants met the study inclusion criteria. Of these subjects, 51% had depressive symptoms at baseline and 23% of participants were less than 95% adherent in the first year of follow-up. The overall all-cause mortality rate was 10%. Multivariate analysis showed that individuals with depressive symptoms and adherence < 95% were 5.90 times (95% confidence interval, 2.55–13.68) more likely to die than adherent patients with no depressive symptoms. The estimated median model-based survival probabilities stratified by adherence and depressive symptoms levels ranged from 81% (interquartile range, 72–89%) for depressive symptoms and adherence < 95% to 97% (interquartile range, 94–98%) for no depressive symptoms and adherence ≥ 95%. Conclusion: The results indicate that both depressive symptoms and adherence were associated with shorter survival among individuals with HIV accessing HAART. Given the high prevalence of depressive symptoms in HIV-positive patients and a strong association with adherence, the findings support improvement in the diagnosis and treatment of depression as well as adherence in order to maximize the effectiveness of HAART.