Background Percutaneous coronary intervention (PCI) had become the major therapeutic procedure for coronary artery disease (CAD), but the high rate of in-stent restenosis (ISR) still remained an unsolved clinical problem in clinical practice. Increasing evidences suggested that diabetes mellitus (DM) was a major risk factor for ISR, but the risk predictors of ISR in CAD patients with DM had not been well characterized. The aim of this study was to investigate the clinical and angiographic characteristic predictors significantly associated with the occurrence of ISR in diabetic patients following coronary stenting with drug-eluting stent (DES). Methods A total of 920 patients with diabetes who diagnosed CAD and underwent coronary DES implantation at Beijing Anzhen Hospital in China were consecutively enrolled from January 2012 to December 2012. Of these, 440 patients underwent the second angiography within >= 6 months due to the progression of treated target lesions. Finally, 368 of these patients who met the inclusion and exclusion criteria were followed up by angiography after baseline PCI. According to whether ISR was detected at follow-up angiography, patients were divided into the ISR group (n = 74) and the non-ISR group (n = 294). The independent predictors of ISR in patients with DM were explored by multivariate Cox's proportional hazards regression models. Results A total of 368 patients (260 women and 108 men) with a mean ages of 58.71 +/- 10.25 years were finally enrolled in this study. Of these, ISR occurred in 74/368 diabetic patients (20.11%) by follow-up angiography. Univariate analysis showed that most baseline characteristics of the ISR and non-ISR group were similar. Patients in the ISR group had significantly higher serum very low density lipoprotein cholesterol (VLDL-C), triglyceride (TG) and uric acid (UA) levels, more numbers of target vessel lesions, higher prevalence of multi-vessel disease, higher SYNTAX score, higher rate of previous but lower rate of drinking compared with patients in the non-ISR group. The independent predictors of ISR in patients with DM after DES implantation included VLDL-C (HR = 1.85, 95% CI: 1.24-2.77, P = 0.002), UA (per 50 mu mol/L increments, HR = 1.19, 95% CI: 1.05-1.34, P = 0.006), SYNTAX score (per 5 increments, HR = 1.34, 95% CI: 1.03-1.74, P = 0.031) and the history of PCI (HR = 3.43, 95% CI: 1.57-7.80, P = 0.003) by the multivariate Cox's proportional hazards regression analysis. Conclusions The increased serum VLDL-C and UA level, higher SYNTAX score and the history of previous PCI were independent predictors of ISR in patients with DM after coronary DES implantation. It provided new evidence for physicians to take measures to lower the risk of ISR for the better management of diabetic patients after PCI.