Peptidyl-prolyl isomerase cyclophilin A (CypA) plays important roles in inflammation. However, little is known about the mechanisms by which CypA exerts its effects. It is secreted in human by monocytes activated by high glucose level. It has a role as an inflammatory mediator in vascular tissue damage. Aim This study aims to compare plasma levels of CypA in type 2 diabetic patients with or without coronary artery disease (CAD) with those in healthy participants to determine the potential role of CypA in promoting vascular disease in diabetic patient and to study the association of high-sensitivity C-reactive protein with CypA levels. Patients and methods The present study was conducted on 80 participants who were divided into four groups: group 1, which included apparently healthy individuals; group 2, which included patients with type 2 diabetes mellitus (DM) without CAD; group 3, which included patients with type 2 DM with CAD; and group 4, which included patients with CAD without DM. The plasma level of CypA was measured using a CypA enzyme-linked immunosorbent assay kit. Results The results showed an increase in the median CypA concentration in all patient groups in comparison with the controls (P< 0.001). Also, there was a statistically highly significant increase in the median CypA concentration in diabetic patients with CAD group when compared with only diabetic patients group (P< 0.001) and in patient with only CAD when compared with diabetic patients with or without CAD (P< 0.001). Conclusion This study demonstrated that CypA has a potential role in promoting vascular disease in diabetic patients and revealed that CypA is a good biomarker for CAD with or without DM better than high-sensitivity C-reactive protein.