Background: Early risk stratification of patients with chest pain may be improved by combining cardiac Troponin I (cTnI) results and ECG findings with markers of left-ventricular dysfunction, inflammation or renal function. Methods: Serial measurements of cTnI were prospectively performed in 452 chest pain patients with a non-diagnostic ECG for AMI and admitted to the coronary care unit. NT-pro BNP, CRP, cystatin C and creatinine-clearance were retrospectively analyzed in admission samples. The prognostic value of these markers alone and in different combinations together with ECG findings was evaluated by multivariate logistic regression models. Results: During follow-up, 14 deaths and 21 myocardial (re)-infarctions occurred. Independent predictors for the combined endpoint of death or (re)-infarction were peak cTnI ≥ 0.1 μg/L within 24 h (OR 3.9, 95% confidence interval [CI]1.5-10.4), cystatin C ≥ 1.28 mg/L (OR 5.6, 95% CI 1.9-16.3) and NT-pro BNP ≥ 550 ng/L (OR 2.7, 95% CI 1.0-7.3). At 2 h from admission, a combination of cTnI ≥ 0.1 μg/L, an abnormal ECG and NT-pro BNP or cystatin C as a third variable resulted in a similar stratification of patients to different risk groups. Conclusion: cTnI, NT-pro BNP and cystatin C are strong risk predictors in patients with chest pain. For pragmatic reasons, a combination of cTnI ≥ 0.1 μg/L, ECG findings and a marker of renal function, preferably cystatin C, appears to be most appropriate for early risk stratification of these patients. © 2007 Elsevier Ireland Ltd. All rights reserved.