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Background : Nosocomial lower respiratory tract infections (nLRTIs) are associated with unfavorable clinical outcomes and significant healthcare costs. nLRTIs include hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and other ICU-acquired pneumonia phenotypes. While risk factors for mortality in these infections are critical to guide preventive strategies, it remains unclear whether they vary based on their requirement of invasive mechanical ventilation (IMV) at any point during the hospitalization. Objectives: This study aims to identify risk factors associated with short- and long-term mortality in patients with nLRTIs, considering differences between those requiring IMV and those who do not. Methods : This multinational prospective cohort study included ICU-admitted patients diagnosed with nLRTI from 28 hospitals across 13 countries in Europe and South America between May 2016 and August 2019. Patients were selected based on predefined inclusion and exclusion criteria, and clinical data were collected from medical records. A random forest classifier determined the most optimal clustering strategy when comparing pneumonia site acquisition [ward or intensive care unit (ICU)] versus intensive mechanical ventilation (IMV) necessity at any point during hospitalization to enhance the accuracy and generalizability of the regression models. Results : A total of 1060 patients were included. The random forest classifier identified that the most efficient clustering strategy was based on ventilation necessity. In total, 76.4% of patients [810/1060] received IMV at some point during the hospitalization. Diabetes mellitus was identified to be associated with 28-day mortality in the non-IMV group (OR [IQR]: 2.96 [1.28-6.80], p = 0.01). The 90-day mortality-associated factor was MDRP infection (1.98 [1.13-3.44], p = 0.01). For ventilated patients, chronic liver disease was associated with 28-day mortality (2.38 [1.06-5.31] p = 0.03), with no variable showing statistical and clinical significance at 90 days. Conclusions : The risk factors associated with 28-day mortality differ from those linked to 90-day mortality. Additionally, these factors vary between patients receiving invasive mechanical ventilation and those in the non-invasive ventilation group. This underscores the necessity of tailoring therapeutic objectives and preventive strategies with a personalized approach.