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Purpose: The primary goal of this analysis was to examine the influence of depression above and beyond the effects of HIV treatment on work activity and function. Methods: We combined data from three longitudinal studies of patients starting antiretroviral therapy (ART) and/or entering HIV care in Uganda. Assessments were conducted at baseline and months 6 and 12. The nine-item Patient Health Questionnaire (PHQ-9) was used to assess depressive symptoms, as well as Major (scores >9) and Minor (scores 5-9) Depression status; work functioning was assessed using a subscale of the Medical Outcomes Study HIV Health Survey (MOS-HIV). Multivariate random-effects logistic regression models for longitudinal data were used to examine the impact of treatment on work status and optimal work functioning, with measures of both baseline and change in physical health functioning, cognitive functioning and depression in the models, controlling for baseline demographics, and CD4 cell count. Results: The sample of 1,731 participants consisted of 1,204 starting ART and 527 not yet eligible for ART. At baseline, 35 % were not working, and 37 % had sub-optimal work functioning. Intention-to-treat analyses revealed that those on ART experienced greater improvement in both work outcomes over 12 months relative to non-ART patients, and that baseline and change in physical health functioning, continuous and categorical depression were all independently associated with improvement in both work outcomes, even after accounting for the direct effect of ART. Conclusions: Improvement in physical and mental health plays a key role in the positive impact of HIV treatment on work activity and function, suggesting potential economic benefits of integrating depression treatment into HIV care. [ABSTRACT FROM AUTHOR]