Aim To investigate the relationship between serum osteoprotegerin (OPG) and in-stent restenosis (ISR) in patients with coronary heart disease complicated with diabetes after percutaneous coronary intervention (PCI). Methods From 1 652 diabetes patients undergoing PCI and follow-up angiography at approximately one year, 135 patients were diagnosed with ISR, while 85 patients without ISR were randomly included as controls. Serum OPG levels and biochemical indexes were examined. General clinical data of the study subjects were collected. Multivariable Logistic regression was used to analyze the independent risk factors of ISR. Results Serum OPG levels were significantly higher in patients with ISR than those without ISR (P＜0.001). Patients with ISR had higher rates of smoking, higher values of serum creatinine, total cholesterol, low density lipoprotein cholesterol (LDLC) and high sensitivity C-reactive protein (hs-CRP), lower values of glomerular filtration rate (GFR), more involved vessels, more severe lesions in coronary arteries, less treatment of dual antiplatelet therapy, diabetes control drugs and statins, and smaller stent diameter as compared with patients without ISR (all P＜0.05). The patients were further divided based upon the tertile distribution of OPG. Multivariable Logistic regression analysis showed that OPG level was an independent determinant of ISR with an odds ratio of 5.349(95%CI:2.049～13.967, P＝0.001) and 2.711 (95%CI:1.095～6.710, P＝0.031) for tertile 3 and 2 compared with tertile 1 after correction of possible confounding factors. Conclusion Serum OPG level is associated with the presence of ISR, and it is an independent risk factor of ISR in diabetes patients.