Symptoms of Human Immunodeficiency Virus (HIV) infection and somatic symptoms of depression overlap, confounding clinical assessments of persons with HIV infection. This research examined the extent of this confounding. In Study 1, 71 persons with HIV infection demonstrated high rates of depression on the Beck Depression Inventory (BDI). However, depression scores correlated with symptoms of HIV infection. In Study 2, 63 persons with HIV infection also demonstrated high rates of depression on the BDI, and depression was again related to symptoms of HIV disease; specifically, persistent fatigue, diarrhea, night sweats, and muscle aches. Principal component factor analyses demonstrated that somatic symptoms of depression were closely associated with number of Acquired Immunodeficiency Syndrome diagnoses, number of HIV-related symptoms, and inversely related to number of T-helper cells. In contrast, cognitive-affective depression was most closely related to anxiety, hypochondriasis, and number of months since tested HIV positive. Results support the conclusion that depression scores require differential interpretations at different stages of HIV disease and that persons who have experienced HIV-related symptoms only be assessed for depression using instruments void of somatic symptoms.