In this study, we investigated the safety and efficacy of fondaparinux sodium in post-percutaneous coronary intervention (PCI) anticoagulation therapy for patients with ST-segment elevation myocardial infarction. There are a total of 200 patients with ST segment elevation myocardial infarction underwent PCI and anticoagulation therapy. They were randomly split into experimental (n=108) and control groups (n=92). The experimental group received postoperative fondaparinux sodium (2.5 mg q.d.), while the control group received enoxaparin (4000 IU q12h). We did not use a loading dose for enoxaparin. Bleeding incidence and major adverse cardiovascular/cerebrovascular events (MACCE) were monitored during hospitalization, and at 1, 3, and 6 months post-surgery. The primary endpoints, including bleeding, mortality, and myocardial infarction during hospitalization, were not significant different between the two groups. For secondary endpoints, the incidence of combined endpoint events at 1 month, 3 months, and 6 months following surgery in the experimental group was lower than in the control group (P < 0.05). According to Cox regression analysis, the risk of bleeding in the experimental group was significantly lower than that in the control group (hazard ratios: 0.506, 95% confidence interval (CI): 0.284-0.900) (P=0.020). The risk of mortality in the experimental group was significantly lower than in the control group (hazard ratio: 0.188, 95% CI: 0.040-0.889) (P=0.035). In summary, perioperative use of fondaparinux sodium during PCI in patients with STEMI in this study was associated with a lower risk of bleeding and death compared to enoxaparin use in the absence of loading dose.