The ongoing COVID-19 pandemic has increased awareness about sex-specific differences in immunity and outcomes following respiratory virus infections. Strong evidence of a male bias in acute COVID-19 disease severity will be presented based on clinical data and preclinical animals models, which illustrate sex differential immune responses against SARS-CoV-2. In addition to biological sex (i.e., differences between males and females based on sex chromosome complement, reproductive tissues, and sex steroid concentrations) , the sociocultural construct of gender (i.e., behaviors, cultural norms, and societal factors that contribute to differences between men and women), along with age, comorbidities, and social determinants of health (e.g., race or ethnicity) also contribute to the male bias in severe acute COVID-19 outcomes. While males suffer worse outcomes from COVID-19 during acute infection, female are more likely to suffer long-term symptoms of post-acute sequalae of SARS-CoV-2 (PASC). Immunological changes associated with pregnancy further contribute to worse outcomes from COVID-19. Infection caused heightened systemic inflammatory responses, including IL-1b, and impaired antibody responses in pregnant women infected with SARS-CoV-2. Preclinical animal models are providing insights into lasting effects of maternal SARS-CoV-2 infection on offspring. The data presented will illustrate our understanding of the pathogenesis of COVID-19 is improved with attention to sex, gender, and women’s health.