Objective To explore the effect of thrombelastography (TEG) guided dual antiplatelet therapy (DAPT) on clinical prognosis of in-stent restenosis (ISR) patients after percutaneous coronary intervention (PCI). Methods A total of 275 patients diagnosed with ISR after PCI by coronary angiography (CAG) who were admitted to the Department of Cardiology, First Medical Center of Chinese PLA General Hospital from January 2017 to January 2020 were recruited in this study. All of them received TEG examination, and according to adenosine diphosphate pathway-induced platelet inhibition rate (ADP inhibition rate) and maximum amplitude of ADP (MA-ADP), the patients were divided into control group (n=184), clopidogrel group (n=57) and ticagrelor group (n=34), being given aspirin combined with clopidogrel or ticagrelor for treatment. All of the patients were followed up every 6 months after discharge, and their long-term prognosis were compared among the 3 groups. SPSS 25.0 software was used for statistical analysis. Logistic regression analysis was employed to screen the risk factors for the prognosis of ISR patients. Results The follow-up time was 15-52 [26 (18,34)] months. The control group exhibited significantly higher ADP inhibition rate than the clopidogrel group and ticagrelor group [(85.64±13.57)% vs (37.60±8.19)% and (22.74±9.76)%; P<0.05). The MA-ADP was significantly higher in the ticagrelor group than the control group and the clopidogrel group [(52.16±4.82) vs (17.01±9.08)and (38.69±4.68)mm; P<0.05]. In the ticagrelor group, the ADP inhibition rate was increased from (22.74±9.76)% to (81.04±15.01)%, and the MA-ADP was decreased from (52.16±4.82) to (17.06±9.26) mm after drug change (P<0.05). The incidence of major adverse cardiovascular events (MACE) and all-cause mortality were significantly higher in the clopidogrel group than the other 2 groups (P<0.05). ADP inhibition rate was a protective factor for re-admission, coronary angiography, re-PCI and cardiovascular death and MACE in patients with ISR after treatment. With the increase of ADP inhibition rate, the MACE rate was decreased obviously (OR=0.56, 95%CI 0.42-0.76; P<0.001). Conclusion The ADP inhibition rate is a protective factor for MACE after ISR treatment. TEG-guided effective DAPT treatment can significantly reduce the incidence rate of MACE and improve the prognosis in ISR patients.