This study investigates the association between circulating sex hormones and the severity of COVID-19 in patients. It was conducted at Barnes Jewish Hospital in St Louis, Missouri, from March to May 2020, with 152 patients (90 men, 62 women) who presented with COVID-19. Testosterone, estradiol, and insulin-like growth factor 1 (IGF-1) concentrations were measured at the time of presentation and at subsequent time points. The primary outcome was severe COVID-19, defined as requiring hospitalization, ICU admission, mechanical ventilation, or death. Results showed that lower testosterone concentrations were associated with increased disease severity and higher levels of inflammatory cytokines in men but not in women. Testosterone concentrations were inversely correlated with interleukin 6, C-reactive protein, interleukin 1 receptor antagonist, hepatocyte growth factor, and interferon γ-inducible protein 10. Estradiol and IGF-1 concentrations were not significantly associated with COVID-19 severity in men. Gene set enrichment analysis revealed upregulation of hormone signaling pathways in monocytes of male patients requiring ICU care compared to those with milder disease. The study suggests that lower testosterone concentrations may play a role in the worse outcomes observed in men with COVID-19, highlighting the need for further clinical trials to test this hypothesis.This study investigates the association between circulating sex hormones and the severity of COVID-19 in patients. It was conducted at Barnes Jewish Hospital in St Louis, Missouri, from March to May 2020, with 152 patients (90 men, 62 women) who presented with COVID-19. Testosterone, estradiol, and insulin-like growth factor 1 (IGF-1) concentrations were measured at the time of presentation and at subsequent time points. The primary outcome was severe COVID-19, defined as requiring hospitalization, ICU admission, mechanical ventilation, or death. Results showed that lower testosterone concentrations were associated with increased disease severity and higher levels of inflammatory cytokines in men but not in women. Testosterone concentrations were inversely correlated with interleukin 6, C-reactive protein, interleukin 1 receptor antagonist, hepatocyte growth factor, and interferon γ-inducible protein 10. Estradiol and IGF-1 concentrations were not significantly associated with COVID-19 severity in men. Gene set enrichment analysis revealed upregulation of hormone signaling pathways in monocytes of male patients requiring ICU care compared to those with milder disease. The study suggests that lower testosterone concentrations may play a role in the worse outcomes observed in men with COVID-19, highlighting the need for further clinical trials to test this hypothesis.