Objective To determine the serum levels of soluble CD40 ligand (sCD40L) and high sensitivity C-reaction protein (hs-CRP) in patients with acute coronary syndrome (ACS) and their clinical significance. Methods A total of 116 ACS inpatients [86 males and 30 females; aged (58.4±10.4)years, ranging from 39 to 78 years] in the Department of Cardiology of Xijing Hospital from May to December 2011 were enrolled in this study. There were 88 cases of unstable angina and 28 cases of acute myocardial infarction. Another 21 patients with normal coronary angiography served as control group (n＝21). Fasting forearm venous blood samples were taken from all patients in the morning for the serum levels of sCD40L and hs-CRP by enzyme-linked immunosorbent assay (ELISA). All patients underwent coronary angiography within 2 to 4 d after admission for the extent of coronary artery stenosis, which were further analyzed with the Gensini scoring system. Results The serum levels of hs-CRP and sCD40L were obviously higher in ACS group than in the controls (P＜0.05). The serum levels of sCD40L and hs-CRP were positively correlated with the Gensini score respectively (r＝0.328, P＝0.000; r＝0.748, P＝0.000). Positive correlation was also found between sCD40l and hs-CRP levels (r＝0.192, P＝0.039). Conclusion The serum levels of sCD40L and hs-CRP are obviously increased in ACS patients, suggesting that CD40/CD40L system may be involved in the development of ACS.