Background: In severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-related respiratory failure, the prognostic value of clinically based or blood-gas-based respiratory indexes is unclear. Objectives: We aimed to assess the prognostic value of Respiratory Index (RI, oxygen saturation [SpO2]/respiratory rate [RR]), RR-oxygenation index (ROX, SpO2/fraction of inspired oxygen [FiO2]/RR), partial pressure of oxygen (PaO2)/FiO2 ratio (P/F), or standard PaO2/FiO2 ratio (<sub>ST</sub>P/F) at admission and of their variation during hospitalization in SARS-CoV-2-related respiratory failure. Methods: In 100 consecutive patients hospitalized due to SARS-CoV-2-related respiratory failure, we assessed the association of RI, ROX, P/F and <sub>ST</sub>P/F, and death; secondary outcome was the composite of 7-day death or intensive care unit (ICU) admission. Results: ROX <3.85 at admission (hazard ratio [HR] 2.95, 95% confidence interval [CI] 1.29–6.77) and decreasing RI or P/F during hospitalization (RI: HR 1.05, 95% CI: 1.00–1.09; P/F: HR 1.01, 95% CI: 1.00–1.02) were predictors of in-hospital death. RI ≤3.8, ROX <3.85, and P/F <100 at admission were predictors for death or ICU admission (RI: HR 3.77, 95% CI: 1.30–10.98; ROX: HR 4.56, 95% CI: 1.90–10.96; P/F: HR 7.37, 95% CI: 1.59–34.2). The decrease of RI (HR 1.14, 95% CI: 1.03–1.25), ROX (HR 1.45, 95% CI: 1.11–1.88), P/F (HR 1.08, 95% CI: 1.01–1.15), or <sub>ST</sub>P/F (HR 1.05, 95% CI: 1.01–1.08) during hospitalization was associated with 7-day death or ICU admission. Conclusions: In patients with SARS-CoV-2-related respiratory failure, easy-to-calculate clinically based respiratory indexes at admission and their variation during hospital stay can be used to assess and monitor the risk for death or ICU admission.