Abstract Background Myocardial infarction with non-obstructive coronary arteries (MINOCA) is a complex and understudied syndrome that disproportionally affects females. Studies to date evaluating sex-differences in ST-segment elevation MINOCA (STE-MINOCA) are limited; therefore, it remains uncertain whether the sex disparities observed in STEMI due to obstructive coronary arteries (STEMI-Obstruction) are also present in STE-MINOCA patients. Objectives Compare clinical characteristics and long-term mortality risk in male versus female patients presenting with STE-MINOCA and STEMI-Obstruction. Methods A multicenter registry-based cohort study enrolled consecutive STEMI patients at three regional, tertiary STEMI centers from 2003 to 2020. STE-MINOCA inluded patients with (1) coronary stenosis less than 60% as determined by coronary angiography, (2) evidence of ischemia with elevated troponin, and (3) no alternative diagnosis. Survival times between males and females with each diagnosis (STE-MINOCA & STEMI-Obstruction) were estimated using the Kaplan Meier method and compared using log-rank tests. The risk of 5-year mortality in patients surviving to discharge was estimated from a Cox regression model with the interaction term for sex and diagnosis STE-MINOCA or STEMI-Obstruction) and adjusted for age, hypertension, diabetes, dyslipidemia, year of event and clustered by the study site. Results Out of 8,566 STEMI patients, 420 (4.9%) had STE-MINOCA of whom 52.9% were female and 8146 (95.1%) had STEMI-Obstruction of whom 29.3% were female. Median follow-up was 7.1 years. Females had significantly higher 5-year mortality risk compared to male counterparts in both STE-MINOCA [HR 2.37 (1.37-4.11, p=0.002)] and STEMI-Obstruction [HR 1.81 (1.59-2.07, p<0.001)] (Figure). After adjusting for confounding variables, the sex difference in mortality risk were not significant: HR 1.04 (0.60-1.81, p=0.89) in STE-MINOCA and HR 1.06 (0.92-1.21, p=0.45) in STEMI-Obstruction. Conclusions In this first study of consecutive STEMI patients examining sex differences by obstructive and non-obstructive mechanism, we report higher 5-year mortality risk in females presenting with STE-MINOCA and STEMI-Obstruction that was attenuated when accounting for age and baseline comorbidities. This study highlights the importance of standardized STEMI protocols to eliminate sex disparities. Abbreviations and Acronyms: Myocardial infarction with non-obstructive coronary arteries (MINOCA), ST-segment elevation MINOCA (STE-MINOCA) STEMI due to obstructive coronary arteries (STEMI-Obstruction)Figure