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Depression is highly prevalent among people living with HIV/AIDS (PLWHA) and has deleterious effects on HIV clinical outcomes. We examined changes in depression symptoms, viral suppression, and CD4+ T cells/μl among PLWHA diagnosed with depression who initiated antidepressant treatment during routine care, and compared the effectiveness of dual-action and single-action antidepressants for improving those outcomes.Comparative effectiveness study of new user dual-action or single-action antidepressant treatment episodes occurring from 2004 to 2014 obtained from the Center for AIDS Research Network of Integrated Clinical Systems.We identified new user treatment episodes with no antidepressant use in the preceding 90 days. We completed intent-to-treat and per protocol evaluations for the main analysis. Primary outcomes, were viral suppression (HIV viral load <200 copies/ml) and CD4+ T cells/μl. In a secondary analysis, we used the Patient Health Questionnaire-9 (PHQ-9) to evaluate changes in depression symptoms and remission (PHQ <5). Generalized estimating equations with inverse probability of treatment weights were fitted to estimate treatment effects.In weighted intent-to-treat analyses, the probability of viral suppression increased 16% after initiating antidepressants [95% confidence interval = (1.12, 1.20)]. We observed an increase of 39 CD4+T cells/μl after initiating antidepressants (30, 48). Both the frequency of remission from depression and PHQ-9 scores improved after antidepressant initiation. Comparative effectiveness estimates were null in all models.Initiating antidepressant treatment was associated with improvements in depression, viral suppression, and CD4+ T cells/μl, highlighting the health benefits of treating depression in PLWHA. Dual and single-action antidepressants had comparable effectiveness.