Objective To investigate the risk factors of dyspnea in acute coronary syndrome (ACS) patients taking antiplatelet drug ticagrelor after percutaneous coronary intervention (PCI). Methods A combination of retrospective and prospective studies was used. A total of 418 ACS patients taking ticagrelor after PCI in the Department of Cardiovasology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from Jan. 2016 to Nov. 2019 were retrospectively included. According to the incidence of dyspnea, the patients were divided into ticagrelor-related dyspnea group and non-dyspnea group. The clinical and laboratory data were collected and compared. In the prospective study, 367 ACS patients taking ticagrelor after PCI in the Department of Cardiovasology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from Jan. to Aug. 2020 were selected. Based on the results of retrospective study and guidelines, the patients were divided into low low-density lipoprotein-cholesterol (LDL-C) group (LDL-C<2.6 mmol/L) and high LDL-C group (LDL-C ≥ 2.6 mmol/L), The clinical data were compared, and the risk factors of ticagrelor-related dyspnea were further analyzed using multiple logistic regression. Results Of the 418 ACS patients in the retrospective study, 71 (17.0%) had ticagrelor-related dyspnea. The ticagrelor-related dyspnea group had more bleeding events (23.9%[17/71] vs 10.1%[35/347], P=0.001) and higher LDL-C level ([2.54±0.88] mmol/L vs[2.32±0.81] mmol/L, P=0.045) compared with the non-dyspnea group. Multiple logistic regression analysis showed that bleeding events (odds ratio[OR]=3.128, 95% confidence interval[CI]1.613-6.065, P=0.001) and elevated LDL-C (OR=1.451, 95% CI 1.071-1.964, P=0.016) were the risk factors of ticagrelor-related dyspnea. Of the 367 ACS patients in the prospective study, 64 (17.4%) had ticagrelor-related dyspnea. The incidence of ticagrelor-related dyspnea was higher in the high LDL-C group than that in the low LDL-C group (23.4%[33/141] vs 13.7%[31/226], P=0.018). At the same time, there were significant differences in the history of smoking, PCI and myocardial infarction, the levels of hypersensitive C reactive protein, fasting blood glucose, total cholesterol, total triglyceride, high-density lipoprotein-cholesterol, left ventricular ejection fraction, and the number of stent implantation between the 2 groups (all P<0.05). Multiple logistic regression analysis showed that smoking history was an independent predictor of ticagrelor-related dyspnea (OR=2.695, 95% CI 1.236-5.878, P=0.013). Conclusion The incidence of dyspnea in ACS patients taking ticagrelor after PCI is 17.4% (64/367). The ACS patients after PCI with serum LDL-C ≥ 2.6 mmol/L are prone to ticagrelor-related dyspnea. Smoking history is an independent predictor of ticagrelor-related dyspnea.