Background: Few studies have examined simultaneously the prognostic value of traditional and emerging biomarkers including atrial natriuretic peptide (ANP) and brain-type natriuretic peptide (BNP), for major cardiovascular disease (CVD) outcomes in patients with stable CVD, and results are equivocal. Design: and Methods: Mid-regional pro-ANP (MR-proANP) and N-Terminal pro-BNP (NT-proBNP), CRP and homocysteine were measured in stable CVD patients (n = 1456; age: 61.8 y) at inclusion in the SU.FOL.OM3 cohort. Prospective association of biomarkers with risk of heart failure, major cardiovascular (non-fatal myocardial infarction, ischemic stroke or death from CVD) or overall cardiovascular event were examined with Cox proportional-hazards analyses. Increase in prediction risk upon addition of biomarker(s) to the traditional risk model was examined by change in C-statistic, NRI and IDI. Results: During follow-up (median: 4.7 y), 40 heart failure, 145 major cardiovascular and 493 overall cardiovascular events were diagnosed. In models adjusted for age, sex, smoking, diabetes, serum creatinine and CVD inclusion criteria, NT-proBNP and CRP associated significantly with heart failure. Both natriuretic peptides predicted the risk of major cardiovascular events in adjusted models; Hazard ratio (HR) and 95% CI for each SD increase in MR-proANP and NT-proBNP were 1.24 (1.04-1.47), and 1.31 (1.09-1.57), respectively. The addition of NT-proBNP to a traditional risk model increased significantly the area-under-curve for heart failure and overall cardiovascular events (by 6 and 12%, respectively); addition of MR-proANP or homocysteine yielded modest (2%) but statistically significant increase for major cardiovascular events. Conclusion: NT-proBNP consistently predicted CVD outcomes and may be useful singly or in combination with MR-proANP for risk-stratification in high-risk patients. (C) 2013 Elsevier Ireland Ltd. All rights reserved.