Objective: To identify sex-specific effects of risk factors for in-hospital mortality among COVID-19 patients admitted to a hospital system in New York City. Design: Prospective observational cohort study with in-hospital mortality as the primary outcome. Setting: Five acute care hospitals within a single academic medical system in New York City. Participants: 3,086 hospital inpatients with COVID-19 admitted on or before April 13, 2020 and followed through June 2, 2020. Follow-up till discharge or death MESHD was complete for 99.3% of the cohort. Results: The majority of the cohort was male TRANS (59.6%). Men were younger (median 64 vs. 70, p<0.001) and less likely to have comorbidities such as hypertension MESHD hypertension HP (32.5% vs. 39.9%, p<0.001), diabetes (22.6% vs. 26%, p=0.03), and obesity MESHD obesity HP (6.9% vs. 9.8%, p=0.004) compared to women. Women had lower median values of laboratory markers associated with inflammation MESHD compared to men: white blood SERO cells (5.95 vs. 6.8 K/uL, p<0.001), procalcitonin (0.14 vs 0.21 ng/mL, p<0.001), lactate dehydrogenase (375 vs. 428 U/L, p<0.001), C-reactive protein (87.7 vs. 123.2 mg/L, p<0.001). Unadjusted mortality was similar between men and women (28.8% vs. 28.5%, p=0.84), but more men required intensive care than women (25.2% vs. 19%, p<0.001). Male TRANS sex was an independent risk factor for mortality (OR 1.26, 95% 1.04-1.51) after adjustment for demographics, comorbidities, and baseline hypoxia MESHD. There were significant interactions between sex and coronary artery disease MESHD (p=0.038), obesity MESHD obesity HP (p=0.01), baseline hypoxia MESHD (p<0.001), ferritin (p=0.002), lactate dehydrogenase (p=0.003), and procalcitonin (p=0.03). Except for procalcitonin, which had the opposite association, each of these factors was associated with disproportionately higher mortality among women. Conclusions: Male TRANS sex was an independent predictor of mortality, consistent with prior studies. Notably, there were significant sex-specific interactions which indicated a disproportionate increase in mortality among women with coronary artery disease MESHD, obesity MESHD obesity HP, and hypoxia MESHD. These new findings highlight patient subgroups for further study and help explain the recognized sex differences in COVID-19 outcomes.