Cross-sectional studies have found that individuals with depressive disorders or symptoms have elevated levels of inflammatory markers predictive of coronary artery disease, including interleukin-6 (IL-6) and C-reactive protein (CRP). Due to the paucity of prospective studies, however, the directionality of the depression-inflammation relationship is unclear. We evaluated the longitudinal associations between depressive symptoms and both IL-6 and CRP among 263 healthy, older men and women enrolled in the Pittsburgh Healthy Heart Project, a 6-year prospective cohort study. During the baseline and follow-up visits, participants completed the Beck Depression Inventory-II (BDI-II) to assess depressive symptoms and underwent blood draws to quantify serum IL-6 and CRP. Path analyses revealed that baseline BDI-II (beta=0.18, p=0.01, DeltaR(2)=0.02) was a predictor of 6-year change in IL-6, even after adjustment for demographic, biomedical, and behavioral factors as well as other negative emotions. Of all the factors examined, only body-mass index was a stronger predictor of IL-6 change than depressive symptoms. In contrast to these results, baseline IL-6 did not predict 6-year change in BDI-II. Evidence of a weak bidirectional relationship between BDI-II and CRP was also observed; however, neither of these longitudinal associations was significant. The present findings indicate that depressive symptoms may precede and augment some inflammatory processes relevant to coronary artery disease among healthy, older adults. Therefore, our results imply that depression may lead to inflammation and that inflammation may be one of the mechanisms through which depression contributes to cardiovascular risk.