AIM: To investigate the effect of CYP2C19 gene polymorphism combined with platelet function test guiding antiplatelet drug selection on gastrointestinal bleeding in elderly patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI). METHODS: A total of 216 elderly patients with ACS who were admitted to our hospital from April 2021 to December 2022 and successfully completed PCI were selected and divided into study group and control group according to the random number table method, with 108 cases in each group. All patients received 4 days the same dose aspirin combined with clopidogrel antiplatelet therapy before surgery. After surgery, CYP2C19 genotype detection was performed on the study group to obtain genotype grouping to distinguish different metabolites. Thromboelastogram (TEG) detection was performed on the patients with intermediate metabolites. According to the results, patients with platelet inhibition rate less than 50% (clopidogrel resistance type) were selected and their medication was changed from aspirin and clopidogrel to aspirin and ticagrelor. The control group was treated with aspirin and clopidogrel. Serum levels of cardiac troponin (cTnI), creatine kinase isoenzyme (CK-MB) and hypersensitive C-reactive protein (hs-CRP) were observed 5 weeks after PCI, and major adverse cardiovascular events (MACE) were observed 1 and 6 months after PCI. The expression of CD62P and fibrinogen receptor 1 (PAC-1) in platelets of the two groups were compared before and after 7 and 14 days of treatment. The platelet aggregation rate of the two groups was compared. Gastrointestinal bleeding events and cardiac emergencies were recorded after treatment. RESULTS: Genetic tests showed that there were 21 cases (19.44%) of ultrafast metabolites and 25 cases (23.15%) of fast metabolites, 42 cases of abnormal metabolites including intermediate metabolites (genotypes accounting for 10.19%, 13.89%, 9.26% and 5.56%, respectively) and 20 cases of slow metabolites (genotypes accounting for 11, respectively). 8.33%, 7.41% and 2.78%). 5 weeks after surgery, the serum levels of cTnI, hs-CRP and CK-MB in the study group were lower than those in the control group (P<0.05, P<0.01). One month after operation, the total incidence of MACE between the observation group and the control group was similar (P>0.05). Six months after operation, the total incidence of MACE in the observation group was significantly lower than that in the control group (P<0.05). The expression levels of CD62P and PAC-1 in the study group were lower than those in the control group on day 7 and day 14 after treatment (P<0.01). The maximum platelet aggregation rate in the study group was lower than that in the control group (P<0.01). The occurrence of cardiac emergencies between the two groups was similar (P>0.05). The number of postoperative gastrointestinal bleeding in the study group was lower than that in the control group (χ2=9.479, P<0.01). CONCLUSION: Aspirin combined with ticagrelor antiplatelet therapy can reduce platelet activity, aggregation rate and gastrointestinal bleeding events in patients with low response to chlorpyrrolore who are co-screened by CYP2C19 genotype and platelet function test.