Abstract Background Sex has consistently been shown to affect COVID-19 mortality, but it remains unclear how each sex’s clinical outcome may be distinctively shaped by risk factors. Methods We studied a primary cohort of 4930 patients hospitalized with COVID-19 in a single healthcare system in New York City from the start of the pandemic till August 5, 2020, and a validation cohort of 1645 patients hospitalized with COVID-19 in the same healthcare system from August 5, 2020, to January 13, 2021. Results Here we show that male sex was independently associated with in-hospital mortality, intubation, and ICU care after adjusting for demographics and comorbidities. Using interaction analysis and sex-stratified models, we found that hypoxia interacted with sex to preferentially increase women’s mortality risk while obesity interacted with sex to preferentially increase women’s risk of intubation and intensive care in our primary cohort. In the validation cohort, we observed that male sex remained an independent risk factor for mortality, but sex-specific interactions were not replicated. Conclusions We conducted a comprehensive sex-stratified analysis of a large cohort of hospitalized COVID-19 patients, highlighting clinical factors that may contribute to sex differences in the outcome of COVID-19.