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The novel coronavirus disease (COVID-19) affected females less than males, as demonstrated by sex-disaggregated data present in the literature. During the first wave, females hospitalized at San Raffaele Hospital, Milan, Italy were few in number, presented symptoms later and had less critical clinical conditions than males. The present study aimed to evaluate the epidemiological status of the female population during the second wave, which occurred in Autumn 2020 in Italy. This prospective cohort study included all patients, with a positive real-time reverse-transcriptase polymerase chain reaction for COVID-19, who attended the emergency department or were hospitalized in wards and/or intensive care unit (ICU) from 29th September 2020 to 29th November 2020. A total of 1216 COVID-19 patients were included, of whom 459 (37.8%) were females. The percentage of females admitted was 41.3% in the first period and 36.3% in the second period, without significant increase over time (p = 0.3). Females accounted for 25% of all COVID-19 intensive care unit admissions. There was significantly sexbased difference in the overall hospital mortality (4.1% for females and 11.3% for males, p < 0.0001). At San Raffaele Hospital, Milan, Italy during the second wave, female patients were few and affected by a less severe form of COVID-19. An increase over time of females hospitalized patients was not reported, unlike what was previously demonstrated during the first wave. [ABSTRACT FROM AUTHOR]