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The current study examined the link between immune functioning (CD4 count) and physical symptoms, as well as the moderating role of optimism and depressive symptoms, in a sample of 99 low income, inner city African American women with HIV. Although there was no main effect of CD4 count on physical symptoms, depressive symptoms moderated the association between CD4 count and physical symptoms. More compromised immune functioning (lower CD4 count) was associated with more physical symptoms under conditions of higher levels of depressive symptoms, but not lower levels of depressive symptoms. This finding was observed using both a self-report measure and a clinician-rating of women's depressive symptoms. There were no main or interactive effects for optimism. Clinical implications and future research directions are presented.