<h3>Objective:</h3> To report the prevalence of acute encephalopathy and outcomes in patients with severe COVID-19, and to identify determinants of 90-day outcomes. <h3>Methods:</h3> Data from adults with severe COVID-19 and acute encephalopathy were prospectively collected for patients requiring intensive care unit management in 31 university or university-affiliated in six countries (France, USA, Colombia, Spain, Mexico, Brazil) between March and September of 2020. Acute encephalopathy was defined, as recently recommended, as subsyndromal delirium or delirium, or as a comatose state in case of severely decreased level of consciousness. Logistic multivariable regression was performed to identify factors associated with 90-day outcomes. A Glasgow Outcome Scale−Extended score (GOS-E) of 1−4 was considered a poor outcome (indicating death, vegetative state, or severe disability). <h3>Results:</h3> Of 4060 patients admitted with COVID-19, 374 (9.2%) experienced acute encephalopathy at or prior to the ICU admission. A total of 199/345 (57.7%) patients had a poor outcome at 90-day follow-up as evaluated by the GOS-E (29 patients were lost to follow-up). On multivariable analysis, age >70 years (odds ratio [OR] 4.01, 95% confidence interval [CI], 2.25−7.15), presumed fatal comorbidity (3.98, 1.68−9.44), Glasgow Coma Scale score <9 before/at ICU admission ICU admission (2.20, 1.22−3.98), vasopressor/inotrope support during ICU stay (3.91, 1.97−7.76), renal replacement therapy during ICU stay (2.31, 1.21−4.50), and CNS ischemic or hemorrhagic complications as acute encephalopathy etiology (3.22, 1.41−7.82) were independently associated with higher odds of poor 90-day outcome. Status epilepticus, posterior reversible encephalopathy syndrome, and reversible cerebral vasoconstriction syndrome were associated with lower odds of poor 90-day outcome (OR 0.15, 95% CI 0.03−0.83). <h3>Conclusions</h3> and Relevance: In this observational study, we found a low prevalence of acute encephalopathy at ICU admission in COVID-19 patients. Over a half of patients with COVID-19 presenting with acute encephalopathy had poor outcomes as evaluated by GOS-E. Determinants of poor 90-day outcome were dominated by older age, comorbidities, degree of impairment of consciousness before/at ICU admission, association with other organ failures, and acute encephalopathy etiology. <h3>Trial Registration:</h3> The study is registered with ClinicalTrials.gov, number NCT04320472
