OBJECTIVE: The increased morbidity and mortality associated with depression is substantial. In this paper, we review evidence suggesting that depression contributes to disease and death through immune dysregulation. METHOD: This review focuses on recent human studies addressing the impact of depression on immune function, and the health consequences of those changes. RESULTS: There is growing evidence that depression can directly stimulate the production of proinflammatory cytokines that influence a spectrum of conditions associated with aging, including cardiovascular disease, osteoporosis, arthritis, type 2 diabetes, certain cancers, periodontal disease, frailty, and functional decline. Additionally, depression can down-regulate the cellular immune response; as a consequence, processes such as prolonged infection and delayed wound healing that fuel sustained proinflammatory cytokine production may be promoted by depression. CONCLUSIONS: These direct and indirect processes pose the greatest health risks for older adults who already show age-related increases in proinflammatory cytokine production. Thus, aging interacts with depression to enhance risks for morbidity and mortality.