Despite mounting evidence that depression increases risk for cardiovascular morbidity and mortality, little is known about the mechanisms responsible for this association. The current study examined the inter-relationships between depression, adiposity, and inflammatory molecules implicated in the pathogenesis of coronary heart disease. One hundred adults were enrolled. Half were clinically depressed; the others were matched controls with no history of psychiatric illness. All subjects were in excellent health, defined as having no acute infectious disease, chronic medical illness, or prescribed medication regimen. Structural equation modeling yielded support for a model in which depressive symptoms promote weight accumulation, which in turn activates an inflammatory response through two distinct pathways: expanded adipose tissue release of interleukin-6 and leptin-induced upregulation of interleukin-6 release by white blood cells (CFI =.99; NNFI =.99; RMSEA =.05). It did not support a sickness behavior model in which the inflammatory molecules arising from expanded adipose tissue promote depressive symptoms.