In this study, males seemed to be at higher risk at all steps of the continuum of COVID-19 disease. The strongest mediating signal, although non-significant, was with inflammatory pathways. Further elucidation of causal pathways connecting gender and COVID-19 severity is required in larger cohorts.

• In this retrospective cohort study, 32,919 males and 34,733 females were included, of whom 1,469 (4.5%) and 1,372 (4.0%) tested positive for SARS-CoV-2, respectively.

• Post-adjusting for age and race/ethnicity, a greater likelihood of testing positive (RR = 1.14), 80% higher risk for severe COVID-19 disease (RR = 1.80) and 58% higher risk for death (RR = 1.58) were present in males vs females.

• Mediation analyses suggested non-significant interventional indirect impacts of male gender on severe COVID-19 illness via increased inflammatory markers, socioeconomic status and comorbidities, but the greatest impact was through the inflammation pathway.