Background: High rate of in?stent restenosis (ISR) remained an unsolved clinical problem in clinical practice, especially among patients with diabetes mellitus (DM). Diabetic patients often had hypertriglyceridemia with elevated levels of very low?density lipoprotein cholesterol (VLDL?C). Increasing evidence suggested that VLDL?C was known as a significant risk factor for atherosclerosis and had been recommended as a treatment target by current dyslipidemia guidelines. However, the role of VLDL?C in the occurrence and development of ISR in coronary artery disease (CAD) patients with DM had not been studied. The aim of this study was to evaluate the association between the elevated levels of VLDL?C and the risk of ISR in CAD patients with DM. Methods: A total of 1390 diabetic patients, who underwent coronary drug?eluting stent (DES) implantation at Beijing Anzhen Hospital and followed up by angiography within 6–24 months, were consecutively enrolled. Patients' demographic and clinical characteristics, including age, gender, CAD risk factors, family history, life style, medical history, and coronary angiographic information, were collected carefully at baseline percutaneous coronary intervention and follow?up angiography. Multivariate Cox's proportional hazards regression modeling using the step?wise method (entry, 0.05; removal, 0.05) was used to determine the independent risk associated with ISR in diabetic patients. Results: Finally, 1206 of patients were included in this study. ISR occurred in 132/1206 diabetic patients (10.9%) by follow?up angiography. Patients with ISR had elevated median serum VLDL?C levels compared with those without ISR (0.65 mmol/L vs. 0.52 mmol/L, P = 0.030). The multivariate regression analysis showed that VLDL?C was significantly associated with the risk of ISR in diabetic CAD patients (hazard ratio [HR] = 1.15, 95% confidence interval [CI]: 1.03–1.29, P = 0.017). The HR for the risk of ISR associated with VLDL?C level ≥0.52 mmol/L was 3.01 (95% CI: 1.24–7.34, P = 0.015). Conclusion: The elevated level of serum VLDL?C was a significant and independent risk factor for ISR in diabetic CAD patients after coronary DES implantation.