Studies comparing outcomes of ICU patients admitted for either COVID-19 or seasonal influenza are limited. Our objective was to describe baseline clinical profiles, care procedures, and mortality outcomes by infection status (influenza vs COVID-19) of patients who received invasive mechanical ventilation in the ICU. DESIGN: Retrospective observational study. SETTING: Data were extracted from the Assistance Publique-Hopitaux de Paris database from September 1, 2016, to April 20, 2021. It includes data from the 39 university hospitals. PATIENTS: A total of 752 influenza adult patients and 3,465 COVID-19 adult patients received invasive mechanical ventilation in one of the ICUs of the Paris area university hospitals, France. INTERVENTION: The characteristics and outcome by infection status were compared. Factors associated with mortality were assessed using Cox proportional hazard models after controlling for potential confounders, including infection status. MEASUREMENTS AND MAIN RESULTS: The median age at admission to the ICU was 67 (interquartile range [IQR], 57-77) and 63 yr (IQR, 54-71 yr) for influenza and COVID-19 patients, respectively. At ICU admission, COVID-19 patients were more frequently obese, more frequently had diabetes mellitus or high blood pressure, and were less likely to have chronic heart failure, chronic respiratory disease, chronic kidney failure, or active cancer than influenza patients. The overall survival at 90 days was 57% for COVID-19 patients and 66% for influenza patients (p < 0.001). In a multivariable Cox model, higher age, organ transplant, severe acute respiratory syndrome coronavirus 2 infection, and chronic kidney failure were associated with shorter survival, whereas obesity and high blood pressure were associated with longer survival after invasive ventilation. CONCLUSIONS: COVID-19 and influenza patients requiring mechanical ventilation in the ICU differed by many characteristics. COVID-19 patients showed lower survival independently of potential confounders.