Background: Endothelial cell-specific molecule 1 (ESM-1 or endocan) is an immunoinflammatory marker strongly associated with inflammation, vascular endothelial dysfunction and atherosclerosis.We explored the relationship between serum endocan concentrations and coronary in-stent restenosis (ISR). Methods: Fifty consecutive patients with ISR and 50 control subjects were included in this study. Clinical data and angiographic characteristics were collected. Serum endocan concentrations were measured using an enzymelinked immunosorbent assay. Results: All included patients were divided into four quartiles based on their concentrations of endocan: quartile 1 (0.62-1.31 ng/mL), quartile 2 (1.33-1.74 ng/mL), quartile 3 (1.75-2.77 ng/mL) and quartile 4 (2.78-4.24 ng/mL). The rates of ISR were 16%, 24%, 68%, and 92%, respectively. The patients in quartile 4 had significantly higher rates of ISR than the other groups (p < 0.001). Logistic regression analysis indicated that endocan concentration [odds ratio = 8.65, 95% confidence interval 3.56-20.94; p < 0.001] was an independent predictor of ISR. Receiver operating characteristic curve analysis was used to explore the relationship between endocan and ISR. Using a cutoff value of 1.625 ng/mL, endocan predicted ISR with a sensitivity of 86% and a specificity of 78%. Conclusions: Our findings suggest that plasma endocan levelsmay be a novel biomarker of endothelial dysfunction in patients with ISR.