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Abstract Background To test whether known prognosticators of COVID-19 maintained their stratification ability across age groups. Methods We performed a retrospective study. We included all patients (n = 2225), who presented to the Emergency Department of the Careggi University Hospital for COVID-19 in the period February 2020—May 2021, and were admitted to the hospital. The following parameters were analyzed as dichotomized: 1) SpO2/FiO2 ≤ or > 214; 2) creatinine 82). The primary end-point was in-hospital mortality. Results By the univariate analysis, the aforementioned dichotomized variables demonstrated a significant association with in-hospital mortality in all subgroups. We introduced them in a multivariate model: in G1 SpO2/FiO2 ≤ 214 (Relative Risk, RR 15.66; 95%CI 3.98–61,74), in G2 creatinine ≥ 1.1 mg/L (RR 2.87, 95%CI 1.30–6.32) and LDH ≥ 250 UI/L (RR 8.71, 95%CI 1,15–65,70), in G3 creatinine ≥ 1.1 mg/L (RR 1.98, 95%CI 1,17–3.36) and CRP ≥ 60 ng/L (RR 2.14, 95%CI 1.23–3.71), in G4 SpO2/FiO2 ≤ 214 (RR 5.15, 95%CI 2.35–11.29), creatinine ≥ 1.1 mg/L (RR 1.75, 95%CI 1.09–2.80) and CRP ≥ 60 ng/L (RR 1.82, 95%CI 1.11–2.98) were independently associated with an increased in-hospital mortality. Conclusions A mild to moderate respiratory failure showed an independent association with an increased mortality rate only in youngest and oldest patients, while kidney disease maintained a prognostic role regardless of age.