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One hundred fifty patients were recruited and categorized into two distinct populations (\u201cA\u201d and \u201cB\u201d), according to the indications given by the World Health Organization. Patients belonging the population \u201cA\u201d presented with mild disease not requiring oxygen support, whereas population \u201cB\u201d presented with a severe disease needing oxygen support. The AUC curve of PaO<jats:sub>2<\/jats:sub>\/FiO<jats:sub>2<\/jats:sub> in the discovery cohort was 0.838 (95% CI 0.771\u20130.908). The optimal cut-off value for distinguishing population \u201cA\u201d from the \u201cB\u201d one, calculated by Youden\u2019s index, with sensitivity of 71.79% and specificity 85.25%, LR+4.866, LR\u22120.339, was\u2009&lt;\u2009274\u00a0mmHg. The AUC in the validation cohort of 170 patients overlapped the previous one, i.e., 0.826 (95% CI 0.760\u20130.891). PaO<jats:sub>2<\/jats:sub>\/FiO<jats:sub>2<\/jats:sub> ratio\u2009&lt;\u2009274\u00a0mmHg was a good predictive index test to forecast the development of a severe respiratory failure in SARS-CoV-2-infected patients. Moreover, our work highlights that PaO<jats:sub>2<\/jats:sub>\/FiO<jats:sub>2<\/jats:sub> ratio, compared to inflammatory scores (hs-CRP, NLR, PLR and LDH) indicated to be useful in clinical managements, results to be the most reliable parameter to identify patients who require closer respiratory monitoring and more aggressive supportive therapies. Clinical trial registration: Prognostic Score in COVID-19, prot. 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