Objective: To examine the prospective association of depressive symptoms with circulating C-reactive protein (CRP) and to determine the direction of that association. Methods: Using data from 2,544 healthy participants in the Coronary Artery Risk Development in Young Adults study (ages, 33-45 years; 55% female; 42% black), we examined the prospective association of depressive symptoms, as measured by the Centers for Epidemiologic Studies Depression Scale, with circulating CRP 5 years later. Results: Depressive symptoms in the Coronary Artery Risk Development in Young Adults study Year 15 predicted CRP at Year 20, independent of demographic characteristics, biological and medical risk factors, health behaviors, and Year 15 CRP. This association, however, was conditional on race such that the increase in CRP with increasing depressive symptoms was present in blacks but not whites. In neither blacks nor whites did Year 15 CRP predict Year 20 depressive symptoms. Among black participants, when examined in separate analyses, higher scores on the depressed affect and somatic symptoms subscales of the Centers for Epidemiologic Studies Depression Scale and lower scores on the positive affect subscale were associated with greater Year 20 CRP. The interpersonal problems subscale was unrelated to CRP. When all four subscale scores were entered simultaneously in the same model, black participants' scores on the positive affect and somatic symptoms subscales emerged as independent predictors of Year 20 CRP, whereas the depressed affect and interpersonal problems subscales did not. Conclusions: Depressive symptoms may be linked more closely to inflammation in blacks than in whites. © 2010 by the American Psychosomatic Society.