Aim To investigate the related factors of in-stent restenosis (ISR) after percutaneous coronary intervention (PCI) in patients with coronary heart disease (CHD). Methods A total of 1342 CHD patients who received PCI in our hospital from January 2007 to January 2016 were studied. These patients were divided into ISR group (≥50% diameter stenosis of in-stent) and non-ISR group according to the result of coronary angiography (CAG). The ISR group included 89 patients (94 with lesions), and the non-ISR group included 1253 patients (1754 with lesions). Retrospective analysis of their blood biochemical index, echocardiographic index, coronary artery lesions, stents, medication compliance and major adverse cardiac events were made by multivariate models to predict the occurrence of ISR. Results The incidence of ISR was 6.6% in the selected patients. The prevalence of diabetes, smoking rate, patients with the discontinuation of clopidogrel in 1 year and discontinuation of aspirin were significantly higher in ISR group, as compared with non-ISR group (P＜0.05). Patients in ISR group taking adequate statin was more than that of non-ISR group (P＜0.05). The complex lesions, reference vessel diameter before procedure, serial stents in ISR group were higher than those in non-ISR group (P＜0.001), the stent length was longer in ISR group than that in non-ISR group (28.43±6.58 mm vs. 26.27±7.08 mm, P＝0.001), the stent diameter (2.92±0.41 mm vs. 3.04±0.43 mm, P＝0.003) and postoperative minimal lumen diameter (MLD) (2.44±0.34 mm vs. 2.57±0.35 mm, P＜0.001) were smaller and the percent of diameter stenosis (8.46% vs. 7.60%, P＝0.018) was significantly greater in ISR group than those in non-ISR group. The acute gain was lower in ISR group than that in non-ISR group (1.77±0.43 mm vs. 1.87±0.43 mm, P＝0.043). Multiariable Logistic regression analysis showed that diabetes, smoking, discontinuing aspirin, diameter or length of previously implanted drug-eluting stents (DES), postoperative MLD, serial stents, and the percent of diameter stenosis were independent risk factors for restenosis after PCI (P＜0.05). In an 8 months follow-up, the incidence of recurrent angina, target lesion revascularization (TLR) and combined major adverse cardiovascular events (MACE) in ISR group was significantly higher (P＜0.001). In the 1 year follow-up, the incidence of recurrent angina, myocardial infarction (MI), TLR, composite MACE were significantly higher in ISR group (P＜0.05). The incidence of stent thrombosis was significantly higher in ISR group (P＜0.001). Conclusions Diabetes, smoking, discontinuing aspirin, the diameter or length of previously implanted DES, serial stents, postoperative MLD and the percent of diameter stenosis are risk factors for the development of ISR. Restenosis after PCI may increase the incidence of MACE.