Introduction The objective of the present study was to evaluate the difference in net clinical benefit of clopidogrel plus aspirin compared with ticagrelor plus aspirin after 12 months in patients in mainland China with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) with newer-generation drug-eluting stents (DESs). Methods In this multicenter, retrospective, real-world study, the data were sourced from three databases: BRIC-ACS(I) study, COSTIC study, and 301 Hospital PCI patient database from January 2014 to October 2017. The primary endpoint of the study was net adverse clinical and cerebral events (NACCE) comprised of all-cause death, non-fatal myocardial infarction (MI), non-fatal stroke or Bleeding Academic Research Consortium (BARC) type >= 2 (excluding BARC type = 4) bleeding, whereas the secondary end point was evaluation of major adverse cardiovascular events (MACE) and BARC type >= 2 bleeding events. Results A total of 7862 ACS patients were included in the final analysis, of whom propensity score matching (PSM) analysis yielded 2165 patients in each cohort. After PSM analysis, cumulative incidence of NACCE was significantly lower with clopidogrel and aspirin than with ticagrelor and aspirin [117 (5.4%) vs. 180 (8.3%), P < 0.001] at 12 months. Effect estimates showed reduced risk of NACCE occurrence in patients treated with clopidogrel and aspirin [adjusted hazard ratio (aHR): 0.61, 95% CI 0.48-0.77, P < 0.001]. Incidence of bleeding was significantly lower in the clopidogrel cohort than in the ticagrelor cohort (aHR: 0.48, 95% CI 0.35-0.66, P < 0.001). Clopidogrel and aspirin therapy was comparable to ticagrelor and aspirin in reducing the incidence of MACE after PSM analysis. Conclusion In Chinese ACS patients who underwent PCI with second-generation DESs, outpatient use of clopidogrel dual antiplatelet therapy (DAPT) was associated with reduction in NACCE and bleeding.