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The differential effect of comorbidities on COVID-19 severe outcomes by sex has not been fully evaluated. To examine the association of major comorbidities and COVID-19 mortality in men and women separately. We performed a retrospective cohort analysis using a large electronic health record (EHR) database in the U.S. We included adult patients with a clinical diagnosis of COVID-19 who also had necessary information on demographics and comorbidities from January 1, 2016 to October 31, 2021. We defined comorbidities by the Charlson Comorb