ABSTRACT: BACKGROUND:Recent studies indicated that females have a lower morbidity, severe cases rate, mortality and better outcome than those of male. However, it remained to be addressed why this was the case. METHODS AND FINDINGS:To find the factors that potentially protect females from COVID-19, we recruited all confirmed patients hospitalized at three branches of Tongji Hospital (n=1902) from January 28 to March 8, 2020, and analyzed the correlation between menstrual status (n=509?including 68 from Mobile Cabin Hospital)/female hormones (n=78)/ cytokines related to immunity and inflammation(n=263), and the severity/clinical outcomes in female patients under 60 years of age.Non-menopausal female patients had milder severity and better outcome compared with age-matched men (p<0.01/p<0.01). Menopausal patients had longer hospitalization times than non-menopausal patients ( hazard ratio [HR], 1.91; 95% confidence interval [CI], 1.06-3.46?p= 0.033). Both anti-müllerian hormone (AMH) and estradiol (E2) showed a negative correlation with severity of infection (AHR=0.146/0.304, 95%CI = [0.026-0.824]/[0.092-1.001], p=0.029/0.05). E2 levels were negatively correlated with IL-2R, IL-6, IL-8 and TNF? in luteal phase (Pearson Correlation=-0.592, -0.558, -0.545, -0.623; p=0.033, 0.048, 0.054, 0.023), and with C3 in follicular phase (Pearson Correlation=-0.651; p=0.030). CONCLUSION:Menopause is an independent risk factor for female COVID-19 patients. AMH and E2 are potential protective factors, negatively correlated with COVID-19's severity, among which E2 is attributed to its regulation of cytokines related to immunity and inflammation. Hormone supplement might be a potential therapy for COVID-19 patients.