Abstract Background: Diabetes is associated with an increased risk of cardiovascular disease and atherosclerosis. Increasing evidence shows that CD40–CD40L interaction plays a crucial role in the pathogenesis of atherosclerosis and coronary artery disease. The purpose of this study was to assess whether CD40 system expressions were disrupted in patients with diabetes. Methods: Sixteen normal controls and 72 patients including 20 with type 2 diabetes mellitus (DM), 15 with type 1 DM, 20 with coronary heart disease (CHD) and 17 CHD with coexisting DM were investigated. The expression of CD40 and CD40L on platelet was analyzed by indirect-immunofluorescence flow cytometry and serum-soluble CD40L level was determined by a commercially available ELISA. Serum of AGE was detected by fluorescence spectroscopy. Results: Type 1 DM, type 2 DM, CHD and CHD Patients with coexisting diabetes showed a significant increase of CD40 (81.8±11.7, 70.7±11.6, 68.5±10.2, 79.9±11.9 MIF, respectively) and CD40L (18.4±5.1, 13.9±4.1, 13.5±3.7, 16.7±4.7 MIF, respectively) coexpression on platelets as well as sCD40L (15.6±3.5, 14.1±3.3, 12.2±3.5, 13.5±3.6 ng/ml, respectively) compared with controls ( p<0.01). A positive correlation was found between serum AGE levels in patients with DM and CD40–CD40L system. We also observed a significant correlation between hemoglobinA1c (HbA1c) concentration and CD40L on platelets ( r=0.71, p<0.001) as well as sCD40L ( r=0.69, p<0.001), but not for CD40 on platelets. Conclusions: Patients with diabetes show increased coexpression of CD40 system, especially CD40L, which may create a proinflammatory and prothrombotic milieu for aggravating the development of atherosclerosis.