OBJECTIVE: Exposure to major life stressors is associated with subsequent enhanced inflammation-related disease processes. Depressive symptoms exacerbate stress-induced inflammatory responses. Moreover, those who report a high degree of perceived health risk before being exposed to a major life stressor such as a disaster are at risk for poor health outcomes. The present study examined whether perceived health risk and depressive symptoms before a disaster were associated with postdisaster inflammation markers. METHODS: The sample included 124 participants (mean [standard deviation] age = 55 [16] years; 69% women). At a baseline visit, participants completed self-report measures of perceived health risk and depressive symptoms (Center for Epidemiologic Studies Depression Scale) in addition to a blood draw for the assessment of inflammation markers (C-reactive protein, tumor necrosis factor receptor 1, and interleukin 6). All participants lived near a large petrochemical complex where an unexpected explosion occurred. A second blood sample was obtained 2 to 6 months after the explosion. RESULTS: No significant differences in inflammation markers were found between predisaster and postdisaster assessment (p > .21). An interaction between predisaster perceived health risk and depressive symptoms in predicting postdisaster circulating inflammation markers was identified (Cohen f = 0.051). Specifically, predisaster perceived health risk was associated with postdisaster circulating inflammation markers if predisaster depressive symptoms were greater than 8.10 on the Center for Epidemiologic Studies Depression Scale. CONCLUSIONS: These findings add to our understanding of the complex interactions between stress, depression, and immune responses. Indeed, findings provide a potential mechanism (i.e., inflammation) explaining the association between exposure to major life stressors and negative mental and physical health outcomes.