ABSTRACTObjective:To identify factors that lead to a positive oxygenation response and predictive factors of mortality after prone positioning. Methods:This was a retrospective, multicenter, cohort study involving seven hospitals in Brazil. Inclusion criteria were being > 18 years of age with a suspected or confirmed diagnosis of COVID-19, being on invasive mechanical ventilation, having a PaO2/FIO2 ratio < 150 mmHg, and being submitted to prone positioning. After the first prone positioning session, a 20 mmHg improvement in the PaO2/FIO2 ratio was defined as a positive response. Results:The study involved 574 patients, 412 (72%) of whom responded positively to the first prone positioning session. Multiple logistic regression showed that responders had lower Simplified Acute Physiology Score III (SAPS III)/SOFA scores and lower D-dimer levels (p = 0.01; p = 0.04; and p = 0.04, respectively). It was suggested that initial SAPS III and initial PaO2/FIO2 were predictors of oxygenation response. The mortality rate was 69.3%. Increased risk of mortality was associated with age (OR = 1.04 [95 CI: 1.01-1.06]), time to first prone positioning session (OR = 1.18 [95 CI: 1.06-1.31]), number of sessions (OR = 1.31 [95% CI: 1.00-1.72]), proportion of pulmonary impairment (OR = 1.55 [95% CI: 1.02-2.35]), and immunosuppression (OR = 3.83 [95% CI: 1.35-10.86]). Conclusions:Our results show that most patients in our sample had a positive oxygenation response after the first prone positioning session. However, the mortality rate was high, probably due to the health status and the number of comorbidities of the patients, as well as the severity of their disease. Our results also suggest that SAPS III and the initial PaO2/FIO2 predict the oxygenation response; in addition, age, time to first prone positioning, number of sessions, pulmonary impairment, and immunosuppression can predict mortality.