Chronic kidney disease (CKD) increases cardiovascular risk and mortality. However, traditional cardiovascular risk factors do not adequately account for the substantial increase in mortality observed in CKD. The aim of this study was to examine the relative contributions of novel cardiovascular risk factors to the risk between CKD and mortality. The study population included 4,680 consecutive new patients from a tertiary care preventive cardiology program from 1996 to 2005. Estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease (MDRD) method. Baseline levels of traditional (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, hypertension, triglycerides, total cholesterol, and fasting glucose) and emerging (apolipoproteins A-I and B, lipoprotein[a], fibrinogen, homocysteine, and high-sensitivity C-reactive protein) risk factors were examined. All-cause mortality was obtained from the Social Security Death Index. There were 278 deaths over a median follow-up period of 22 months. CKD (estimated glomerular filtration rate ≤60 ml/min/1.73 m2) was strongly associated with mortality after adjusting for traditional cardiovascular risk factors (hazard ratio 2.31, 95% confidence interval 1.77 to 3.11, p <0.001) and with the addition of propensity score (hazard ratio 2.33, 95% confidence interval 1.75 to 3.10, p <0.001). Of all the traditional and emerging risk factors monitored, only the addition of homocysteine and fibrinogen significantly attenuated the association between CKD and mortality (adjusted hazard ratio 1.73, 95% confidence interval 1.23 to 2.34, p <0.001), explaining 38% of the attributable mortality risk from CKD. A significant interaction (p = 0.004) between homocysteine and estimated glomerular filtration rate was observed whereby the annual mortality rate in subjects with CKD with homocysteine <10 μmol/L (the bottom tertile) was similar to those with normal renal function (1% per year), whereas homocysteine levels ≥12.5 μmol/L (the top tertile) were associated with a sevenfold greater mortality risk. In conclusion, homocysteine and fibrinogen levels explain nearly 40% of the attributable mortality risk from CKD.