The study examined gender differences in 689 inpatients with COVID-19 in an Italian hospital during February and March 2020. Women comprised 39% of the cohort and were significantly older and frailer than men, with 15% of women having a high frailty score (Rockwood ≥ 7) compared to 5% of men. Despite older age and poorer health status, women showed less severe changes on lung CT images (score 25 vs. 30), better oxygenation and a weaker inflammatory response with lower values of inflammatory markers (CRP, LDH, CPK). Women were hospitalized shorter (5 vs. 6 days) and had lower adjusted mortality. Multivariable analysis confirmed that female gender had an independent protective effect (OR 0.597), which was mediated by less severe lung involvement and an attenuated inflammatory response. The findings suggest that sex-related biological differences influence the course of COVID-19 and may be important for a personalized approach to treatment and risk stratification of patients.