Elevated soluble CD40 ligand (sCD40L) levels are associated with an increased risk of cardiovascular events in patients with acute coronary syndromes and in middle-aged healthy women. However, the relationship between sCD40L and global risk assessment remains unclear. The present study was designed to examine the relationship between sCD40L and Framingham Coronary Heart Disease Risk Scores (FCRS) in healthy middle-aged men. The study population consisted of 400 active and retired male firefighters, with no previous history of cardiovascular disease, as part of the Firefighters and Their Endothelium (FATE) study. FCRS correlated poorly with sCD40L levels (p=0.14). Soluble CD40L concentrations correlated only with total (r=0.105; p=0.035) and LDL cholesterol (r=0.104; p=0.039), and CRP levels (r=0.11; p=0.03). Compared with participants with sCD40L levels <4.36 ng/mL (75th percentile), participants with sCD40L levels >4.36 ng/mL had higher total (p=0.016) and LDL cholesterol (p=0.018), CRP levels (p=0.034) and FCRS (p=0.012). Multivariate analysis revealed that CRP level was the only parameter that independently correlated with the sCD40L levels (p=0.032). This is the first study to evaluate the relationship between sCD40L levels and Framingham global risk assessment in a large cohort of otherwise healthy individuals. We demonstrate that sCD40L levels poorly correlate with both the individual components and the calculated FCRS. Long-term follow-up of the FATE study will shed light on whether the predictive value of sCD40L is independent of Framingham based global risk assessment.