BACKGROUND : Current assessment tools for patients with acute chest pain are either traumatic (coronary angiography) or unreliable (measurement of cardiac troponin concentrations). We investigated whether the novel cardiovascular stress markers, serum growth differentiation factor-15 (GDF-15), Krüppel-like factor 4 (KLF4) and growth arrest-specific 6 (gas6) may be useful biomarkers of coronary artery disease (CAD). METHODS : A total of 350 male patients were enrolled, 198 with CAD and 152 controls, based on coronary angiography. GDF-15, KLF4 and gas6 concentrations were measured using commercial enzyme-linked immunosorbent assay kits. Multivariate logistic regression and multivariate linear regression were performed to evaluate potential associations of GDF-15, KLF4 and gas6 with risk of CAD or CAD severity. RESULTS : Serum GDF-15, KLF4 and gas6 concentrations were significantly higher in male patients with CAD than in control subjects (P < .05), and they correlated significantly with involvement of coronary vessels (P < .05). After adjusting for confounding factors, we found that circulating GDF-15 concentrations remained positively associated with the presence of CAD (odds ratio [OR] per 1-standard deviation [SD] increase, 3.182; 95% confidence interval [CI] 1.586 to 6.382; P = .001), as did KLF4 concentrations (OR per 1-SD increase, 13.05; 95% CI 2.940 to 57.921, P = .001). Moreover, circulating GDF-15 concentrations were positively associated with the Gensini score (estimated SD change per 1-SD increase, 22.091; 95% CI 9.147 to 35.035, P = .001), as were KLF4 concentrations (estimated SD change per 1-SD increase, 27.996; 95% CI 10.082 to 45.910, P = .002). Gas6, in contrast, showed no relationship to presence of CAD or Gensini score. UNASSIGNED : In this case-control study, increased concentrations of circulating GDF-15 and KLF4 were significantly associated with the presence and severity of CAD.