Résumé : Purpose: To investigate the possible association between ventilatory settings on the first day of invasive mechanical ventilation (IMV) and mortality in patients admitted to the intensive care unit (ICU) with severe acute respiratory infection (SARI). Materials and methods: In this pre-planned sub-study of a prospective, multicentre observational study, 441 patients with SARI who received controlled IMV during the ICU stay were included in the analysis. Results: ICU and hospital mortality rates were 23.1 and 28.1%, respectively. In multivariable analysis, tidal volume and respiratory rate on the first day of IMV were not associated with an increased risk of death; however, higher driving pressure (DP: odds ratio (OR) 1.05; 95% confidence interval (CI): 1.01–1.1, p = 0.011), plateau pressure (Pplat) (OR 1.08; 95% CI: 1.04–1.13, p < 0.001) and positive end-expiratory pressure (PEEP) (OR 1.13; 95% CI: 1.03–1.24, p = 0.006) were independently associated with in-hospital mortality. In subgroup analysis, in hypoxemic patients and in patients with acute respiratory distress syndrome (ARDS), higher DP, Pplat, and PEEP were associated with increased risk of in-hospital death. Conclusions: In patients with SARI receiving IMV, higher DP, Pplat and PEEP, and not tidal volume, were associated with a higher risk of in-hospital death, especially in those with hypoxemia or ARDS.