Background: To our knowledge, no clinical study has been investigated the relationship between thrombospondin-1 (TSP-1), diabetes mellitus (DM) and atherosclerosis. This study was aimed to reveal the relationship among plasma TSP-1 concentration, DM, and coronary artery disease (CAD). Methods: The study involved 400 subjects (215 men, 185 women) with suspected CAD, who were undergone coronary angiography to evaluate effort angina. Each patient was divided into four groups as follows: DM(-) and CAD(-), DM(-) and CAD(+), DM(+) and CAD(-), and DM(+) and CAD(+). Results: We found that plasma TSP-1 levels were higher in patients with DM(+) and CAD(+) (n=109) than other patients (n=291) (p<0.01). Multivariate analysis showed that high sensitivity C-reactive protein (OR 1.508, 95% CI 1.040-2.186), glycated hemoglobin (HbA1c) (OR 1.461, 95% CI 1.092-1.956) and plasma TSP-1 (OR 1.005, 95% CI 1.002-1.009) levels were independently associated with the development of CAD in DM patients. Conclusion: Plasma TSP-1 levels were higher in patients with DM(+) and CAD(+) than in other patients, and plasma TSP-1 levels were independently associated with the development of CAD in DM patients. These findings suggest that plasma TSP-1 may contribute to CAD development in DM patients.