| Summary: | <i>Background:</i> Since the outbreak of the COVID-19 pandemic, a growing number of evidence suggests that COVID-19 presents sex-dependent differences in clinical course and outcomes. Nevertheless, there is still an unmet need to stratify the risk for poor outcome at the beginning of hospitalization. Since individual C<sub>2</sub>HEST components are similar COVID-19 mortality risk factors, we evaluated sex-related predictive value of the score. <i>Material and Methods:</i> A total of 2183 medical records of consecutive patients hospitalized due to confirmed SARS-CoV-2 infections were analyzed. Subjects were assigned to one of two of the study arms (male vs. female) and afterward allocated to different stratum based on the C<sub>2</sub>HEST score result. The measured outcomes included: <i>in-hospital</i>-mortality, <i>three-month-</i> and <i>six-month-</i>all-cause-mortality and <i>in-hospital</i> non-fatal adverse clinical events. <i>Results:</i> The C<sub>2</sub>HEST score predicted the mortality with better sensitivity in female population regarding the short- and mid-term. Among secondary outcomes, C<sub>2</sub>HEST-score revealed predictive value in both genders for pneumonia, myocardial injury, myocardial infarction, acute heart failure, cardiogenic shock, and acute kidney injury. Additionally in the male cohort, the C<sub>2</sub>HEST value predicted acute liver dysfunction and all-cause bleeding, whereas in the female arm-stroke/TIA and SIRS. <i>Conclusion:</i> In the present study, we demonstrated the better C<sub>2</sub>HEST-score predictive value for mortality in women and illustrated sex-dependent differences predicting non-fatal secondary outcomes.
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