Background: Atherosclerosis is widely accepted as a chronic inflammatory disease. Research paid much attention to sensitive specific serum biomarkers for vulnerable plaques. The markers not only serve as diagnostic tools for the identification of patients with acute coronary syndrome (ACS), but also help us to identify hie-h-risk patients. However, the existing data are limited and have been conflicting. Hypothesis: Circulating interleukin-6 (IL-6), soluble CD40 ligand (sCD40L), metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) might correlate with the onset and the cardiac mortality of patients with ST-segment elevation myocardial infarction (STEMI). Methods: Serum levels of IL-6, sCD40L, MMP-9, and TIMP-1 were measured by sandwich enzyme-linked immunosorbent assay (ELISA) in 263 patients with STEMI and 262 age- and gender-matched control subjects without coronary artery disease (CAD). The patients with STEMI were then followed prospectively for 24 mo for the Occurrence of cardiac mortality. Results: Compared with the control subjects, patients with STEMI exhibited higher levels of IL-6 (p < 0.001), sCD40L (p < 0.001), MMP-9 (p < 0.001), TIMP-1 (p = 0.045), and MMP-9/TIMP-1 ratio (p = 0.007). Significant and positive correlations between MMP-9 and TIMP-1 (r = 0.610, p <= 0.001), IL-6 and creatine kinase (CK) (r = 0.159, p = 0.022), and IL-6 and Troponin-I (TnI) (r = 0.141, p = 0.042) were observed by Spearman's correlations analysis. Logistic regression analysis revealed that IL-6 significantly and independently correlated with the occurrence of STEMI, and IL-6 was an independent predictor for cardiac mortality during a 24-mo follow-up in patients with STEMI. Conclusion: The present study indicates that elevated admission level of IL-6, but not of sCD40L, MMP-9, or TIMP-1, might indicate the onset of STEMI, and could provide prognostic value for future cardiac mortality within 2 y in patients with STEMI.