ObjectiveTo assess the correlation of dead space fraction (VD/VT) measured through time capnography, corrected minute volume (CMV) and ventilation ratio (VR) with clinical outcomes in COVID-19 patients requiring invasive mechanical ventilation. DesignObservational study of a historical cohort. SettingUniversity hospital in Medellin, Colombia. ParticipantsPatients aged 15 and above with a confirmed COVID-19 diagnosis admitted to the ICU and requiring mechanical ventilation. InterventionsMeasurement of VD/VT, CMV, and VR in COVID-19 patients. Main variables of interestVD/VT, CMV, VR, demographic data, oxygenation indices and ventilatory parameters. ResultsDuring the study period, 1047 COVID-19 patients on mechanical ventilation were analyzed, of whom 446 (42%) died. Deceased patients exhibited a higher prevalence of advanced age and obesity, elevated Charlson index, higher APACHE II and SOFA scores, as well as an increase in VD/VT ratio (0.27 in survivors and 0.31 in deceased) and minute ventilation volume on the first day of mechanical ventilation. The multivariate analysis revealed independent associations to in-hospital mortality, higher VD/VT (HR 1.24; 95%CI 1.003–1.525; p = 0.046), age (HR 1.024; 95%CI 1.014–1.034; p < 0.001), and SOFA score at onset (HR: 1.036; 95%CI: 1.001–1.07; p = 0.017). ConclusionsVD/VT demonstrated an association with mortality in COVID-19 patients with ARDS on mechanical ventilation. These findings suggest that VD/VT measurement may serve as a severity marker for the disease.