Objective To investigate the current status and related factors of in-stent restenosis (ISR) in patients with coronary heart disease (CHD) undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES). Methods A total of 536 CHD patients undergoing PCI in our hospital from June 2018 to June 2021 were enrolled as the study subjects. According to their age, they were divided into elderly group (n=330) and young and middle-aged group (n=206). At 6-12 months of follow-up, the incidence rate of DES-ISR was observed in the patients of different age groups. According to the imaging results, the patients were divided into ISR group and non-ISR group, and the related factors affecting DES-ISR were analyzed. SPSS statistics 20.0 was used for statistical analysis. Data comparison between two groups was performed using student′s t test or Chi-square test depending on data type. Results The incidence rate of DES-ISR after PCI was 18.18% (60/330) in the elderly group and 15.53% (32/330) in the young and middle-aged group, and there was no statistical significance between the two groups. The elderly ISR group had obviously larger proportions of diabetes mellitus, bifurcation, calcification, diffuse stenosis, poor postoperative medication compliance, and under-expansion of the stent and stent fractures, higher preoperative Gensini score, larger stent diameter and longer stent length and higher stent number, and higher count fasting blood glucose level when compared with those without ISR group (all P<0.05). In the young and middle-aged patients with ISR, larger proportions of hypertension, smoking and drinking, and higher Gensini score and low-density lipoprotein level were observed than in those without ISR (all P<0.05). Conclusion The related factors affecting the incidence of DES-ISR after PCI in CHD patients of different age groups are not the same. The risk of DES-ISR after PCI is mainly related to the severity of coronary artery lesion and stent implantation status in the elderly, while postoperative bad living habits in the young and middle-aged patients.