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Depression is found frequently with HIV/AIDS, but the reasons for this association are unclear. An important question is the possible effect of immunological factors on depression. In 201 persons with HIV/AIDS being seen in clinics in Uganda a study was mounted to address this issue. Information on depression was collected, and the diagnosis of major depressive disorder (MDD) was based on DSM-IV criteria. The frequency of MDD was 30.8% in this population. Laboratory data were collected and included Interleukin 6 (IL-6), Tumor Necrosis Factor-Alpha (TNF-alpha) and C-Reactive Protein (CRP). The analysis controlled for study site, sex, age, and education. Odds of MDD increased as the level of IL-6 increased. In a similar manner as the TNF-alpha increased the odds of MDD increased. However, there was no indication that MDD was associated with the level of CRP. The association of IL-6 and TNF-alpha with MDD suggests that a pro-inflammatory mechanism may be part of the explanation of the association.