Coronary artery disease (CAD) is the leading cause of death in patients with end-stage renal disease (ESRD). Recent evidence suggests that the expression of Fas, a molecule implicated in the initiation of apoptosis in various cell types, is increased at sites of atherosclerotic plaques. However, the significance of plasma levels of the soluble form of Fas (sFas) and its ligand (sFas-L) as markers of atherosclerosis has yet to be defined. The present report is a cross-sectional analysis of baseline data from an ongoing prospective study designed to evaluate the role of sFas and sFas-L as markers of CAD in ESRD. We evaluated the association between plasma levels of sFas and sFas-L and evidence of CAD in a cohort of 107 chronic hemodialysis patients. Plasma levels of sFas were significantly greater (P = 0.04) among subjects with (n = 64) than without evidence of CAD (n = 43). Plasma levels of sFas-L were similar in both groups. Using multivariate analysis, sFas level was found to be independently associated with CAD (P = 0.01) after adjustment for classic risk factors for CAD (hyperlipidemia, diabetes, hypertension, and smoking), markers of inflammation (C-reactive protein [CRP], intercellular adhesion molecule 1), and other confounders. An increase of one quintile in plasma concentration of sFas was associated with an odds ratio for CAD of 1.64 (95% confidence interval, 1.11 to 2.41). Models that incorporated sFas were significantly better at identifying patients with CAD than models limited to classic risk factors for atherosclerosis, alone (P = 0.008) or in combination with CRP levels (P = 0.006). In summary, increased plasma levels of sFas are associated with CAD in stable patients with ESRD. These results suggest that sFas may represent a novel and independent marker of CAD.