AIMS: Endometriosis frequently affects reproductive aged females and is associated with increased cardiovascular disease risk. The aims of this study were (i) to confirm the relationship between cardiovascular disease and endometriosis and (ii) to test whether aspirin modified the effect of endometriosis on cardiovascular disease risk. METHODS AND RESULTS: A longitudinal cohort study was conducted using data from the California Teachers Study from enrolment (1995-1996) through the current administrative end follow-up (31 December 2020). Primary outcome was any incident major adverse cardiovascular event (MACE) defined using validated ICD-9/ICD-10 codes for stroke, myocardial infarction, and coronary heart disease. Inverse probability (IP) weights were used to estimate the causal effect of self-reported endometriosis on cardiovascular events. Of the included 120 435 participants, 13 754 (11.4%) reported history of endometriosis. There were 2159 admissions for MACE in the endometriosis group vs. 16 632 in the non-endometriosis group. After controlling for demographics and vascular comorbidities, risk of MACE was higher in the endometriosis group than in the non-endometriosis group [IP-weighted hazard ratio (HR) 1.10, confidence interval (CI) 1.04-1.15], particularly in participants <
40 years of age (IP-weighted HR 1.48, CI 1.08-2.02). Aspirin use did not modify the effect of endometriosis on MACE ( CONCLUSION: In a large American cohort, endometriosis was associated with increased risk of adverse cardiovascular events, especially in younger participants. Aspirin did not modify this risk. Research to determine how to best reduce cardiovascular risk in endometriosis is warranted.