Although race/ethnicity is associated with substantial differences in risk for depression and other diseases of aging in the United States, the processes underlying these health disparities remain poorly understood. We addressed this issue by examining how levels of a robust marker of inflammatory activity, C-reactive protein (CRP), and depression symptoms varied across racial/ethnic groups. Additionally, we tested whether the inflammation-depression association differed across groups. Data were drawn from the Chicago Community Adult Health Survey, an epidemiological survey examining biopsychosocial factors affecting health and well-being. Participants were 3105 Chicago community adults, of which 610 provided blood samples and were included in analyses. C-reactive protein was assayed from blood samples, and depression symptoms were assessed using the 11-item Center for Epidemiologic Studies-Depression scale. Race/ethnicity was self-reported and consisted of Black, Hispanic, White, and other racial/ethnic groups. Results revealed that these racial/ethnic groups differed in terms of both their CRP and depression levels. Specifically, Black Americans exhibited higher levels of CRP as compared to White and other race/ethnicity Americans. Moreover, Black Americans exhibited more depression symptoms than Hispanic Americans. Finally, we found that inflammatory levels were strongly related to depression symptoms but only for Black Americans, with CRP alone accounting for 8% of the variance in depression symptoms in this subgroup. These data thus point to a biological process that may help to explain disparities in mental health outcomes across race/ethnicity in the United States. At the same time, additional research is needed to understand the social and structural factors driving these effects.