Objective To explore the risk factors of in-stent restenosis in coronary artery disease (CAD) patients with CYP2C19*1/ *1. Methods The population diagnosed with CAD subsequently underwent PCI, followed by CYP2C19 genotype examination. 127 patients with CYP2C19*1/ *1 followed up 1 year after PCI in our hospital were divided into ISR group (n = 47) and control group (n = 76) according to absence or presence of in-stent restenosis (the restenosis was defined as the reduction of lumen diameter ≥ 50%). The basic clinical data, laboratory results and medication and PCI of the two groups were retrospectively analyzed to figure out the etiological risk factors of in-stent restenosis in CAD patients with CYP2C19*1/ *1. Results Based on bivariate analysis, we found several independent variables (P > 0.05) including age, hypertension, BMI, smoking and drinking history. The independent variables with results of bivariate analysis of P < 0.05 included DM, physical exercise, TG, TBIL, FIB, and the stent length, diameter and number. A multivariate logistic regression analysis showed that such variables including DM,TG,FIB, stent length were independent predictors of ISR (P < 0.05). On the contrary, exercise and stent diameter may be the protective factor (P<0.05). Conclusions Clinical treatment for patients with high risk factors including improved life style, strengthened biochemical indicators monitoring, a reasonable treatment and appropriate stent placement according to individual coronary artery lesions , is expected to reduce the incidence of in-stent restenosis and improve the prognosis.