Plasma D-dimer levels, the primary degradation product of cross-linked fibrin, are elevated in acute coronary syndrome (ACS). However, the role of D-dimer in patients presenting to the Emergency Department with ACS and normal cardiac enzymes is unknown. We conducted a prospective, observational study in the Emergency Department of a major tertiary university-affiliated center. The study included 124 patients presented to the Emergency Department with ACS and normal cardiac enzymes. Blood samples were collected and assayed for D-dimer levels with the enzyme-linked immunosorbent assay (ELISA) test. The D-dimer values were correlated with the clinical, laboratory and electrocardiographic findings on admission, as well as with the catheterization findings and with hospital length of stay. ELISA D-dimer levels positively correlated with sex, hypertension and smoking (r = -0.27, P = 0.002; r = 0.33, P = 0.0002; and r = -0.24, P = 0.007, respectively). Significant correlation was also observed between ELISA D-dimer and cardiac medications including β-blocker (r = 0.22, P = 0.01), aspirin (r = 0.18, P = 0.04), nitrate (r = 0.20, P = 0.002), acute phase reactants fibrinogen (r = 0.45, P = 0.0001) and C-reactive protein (r = 0.29, P = 0.004), ischemic electrocardiographic changes (r = 0.21, P = 0.02) and length of stay (r = 0.29, P = 0.001). The catheterization findings were also correlated with the ELISA D-dimer levels (r = 0.31, P = 0.02). The ELISA D-dimer test may add important clinical data concerning patients with ACS and normal cardiac enzymes.