Objective: Slow coronary flow (SCF) is an angiographic finding characterized with delayed opacification of epicardial coronary arteries without obstructive coronary disease. CD40/CD40 ligand (CD40L) signaling seems closely related to atherosclerosis due to increased inflammation and prothrombotic state. We investigated whether soluble CD40 (sCD40), an indirect marker of CD40/CD40L dyad, is related to SCF. Methods: The present study was cross-sectional and observational, consisting of seventy individuals who underwent coronary angiography with suspicion of CAD and had angiographically normal coronary arteries of varying coronary flow rates. The relationship between sCD40, C-reactive protein (CRP) and SCF phenomenon was investigated. Fifty patients with isolated SCF (mean age: 56±10 years) and 20 age- and gender-matched control participants with normal coronary flow (NCF) and normal coronary arteries (NCA), (mean age: 55±10 years) were included in the study. We used logistic regression analysis to determine the predictors of SCF. Results: The clinical characteristics were not statistically significant different between SCF and NCA group. Serum CRP levels were also similar between two groups. Serum sCD40 level was significantly higher in the SCF group compared to control group (74±31 vs. 59±16 pg/mL, p=0.014). In multiple regression analyses, mean coronary diameter strongly (OR: 7.358, 95% CI: 1.990-27.20, p=0.003) and sCD40 (OR: 1.044, 95% CI: 1.006-1.084, p=0.023) weakly predicted SCF.Conclusion: This study revealed, significantly increased serum sCD40 levels in patients with SCF. Although we cannot conclude the underlying pathological process of SCF, we believe that these findings may be pivotal for further studies searching the specific roles of CD40/CD40L signaling on SCF phenomenon in coronary vasculature.