The prevalence of thrombophilia among patients who are hospitalized with acute coronary syndrome (ACS) and whether the condition affects outcomes is unknown. We conducted a retrospective cohort study of patients hospitalized with ACS by analyzing data from the United State National Inpatient Sample (NIS) between 2016 and 2021. Multiple logistic and linear regressions were used to determine the association between thrombophilia and in-hospital mortality, length of stay and cost. There were a total of 5,627,065 hospital admissions with ACS and 43,040 had thrombophilia (0.76%). Patients with thrombophilia were younger (median age 66 vs. 69 years, p <
0.001) and a lower prevalence of hypertension (76.9% vs. 81.8%, p <
0.001), hypercholesterolemia (54.7% vs. 62.9%, p <
0.001), and diabetes mellitus (39.0% vs. 42.0%, p <
0.001). Fewer patients underwent coronary angiography (40.1% vs. 49.6%, p <
0.001), percutaneous coronary intervention (25.3% vs. 34.4%, p <
0.001), and coronary artery bypass grafting (4.7% vs. 6.5%, p <
0.001). The in-hospital mortality rate was significantly higher in the patients with thrombophilia (13.2% vs. 8.4%, p <
0.001) as well as higher length of stay (median 5 vs. 3 days, p <
0.001) and costs (median 0,744 vs. 6,907, p <
0.001). On multivariable analysis, thrombophilia was associated with increased in-hospital mortality (OR 1.52 95%CI 1.42-1.63, p <
0.001), length of stay (coefficient 2.14 95%CI 1.99 to 2.29, p <
0.001) and cost (coefficient ,123 95%CI 7,477 to 8.768, p <
0.001). Patients with thrombophilia and ACS have less traditional risk factors for coronary heart disease but a greater mortality, length of stay and cost compared to ACS patients without thrombophilia.