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This study assessed the relationship between anti-thrombotics and major adverse cardiovascular events (MACE) in patients with anti-phospholipid syndrome (APS). We included 13 947 subjects with APS from the National (Nationwide) Inpatient Sample (NIS) database for 2016–2018, and collected relevant covariates and demographic data using ICD-10 codes. Our two primary outcomes were MACE and death. We performed multivariate logistic regression analysis to assess the impact of various anti-thrombotic regimens on MACE/death in our primary cohort and high-risk subgroups. Patients on anti-coagulants had significantly reduced odds of MACE [odds ratio (OR) 0.68, 95% confidence interval (CI) 0.62–0.76, p < 0.001] as well as each of its subcomponents. Those not on any anti-coagulants had significantly increased odds of MACE (OR 1.47, 95% CI 1.24–1.72, p < 0.001). No significant association was found between anti-platelet use and the odds of MACE (p > 0.05). Patients on anti-coagulants were the only class that appeared to have a mortality benefit with reduced odds for death (OR 0.64, 95% CI 0.49–0.84, p = 0.001). In the subgroups at higher risk for MACE (those with atrial fibrillation and thrombocytopenia), full anti-coagulation therapy was also the only anti-thrombotic class that significantly affected the odds of MACE, with a protective effect on MACE, but had no mortality benefit. Patients with APS are most likely to benefit from anti-coagulant therapy in reducing MACE. Furthermore, anti-platelets alone or in combination with anti-coagulants are probably not beneficial in MACE reduction and may even increase risk. [ABSTRACT FROM AUTHOR]