ABSTRACT Background: Sepsis-associated encephalopathy (SAE) is a dysfunction of the central nervous system experienced during sepsis with variable clinical and pathophysiologic features. We sought to identify distinct SAE phenotypes in relation to clinical outcomes. Methods: The Medical Information Mart for Intensive Care IV (MIMIC-IV) database and the eICU database were used to conduct a retrospective cohort study. Adult sepsis patients were included and SAE was defined as having a Glasgow Coma Scale (GCS) score ˂15 or delirium. The following our clinical phenotypes were defined as: ischemic-hypoxic, metabolic, mixed (ischemic-hypoxic and metabolic), and unclassified. The primary outcome was in-hospital mortality. Results: The study enrolled 4,120 sepsis patients, 2,239 from MIMIC-IV (including 1,489 patients with SAE, 67%), and 1,881 from eICU (1,291, 69%). For the SAE cohort, 2,780 patients in total were enrolled (median age, 67 years; interquartile range, 56–76.8; 1,589 (57%) were male; median GCS score was 12 [8–14]; median Sequential Organ Failure Assessment score was 6 [4–9]). The SAE phenotype distributions between the MIMIC-IV and eICU cohorts were as follows (39% vs. 35% ischemic-hypoxic, P = 0.043; 38% vs. 40% metabolic, P = 0.239; 15% vs. 15% mixed, P = 0.972; 38% vs. 40% unclassified, P = 0.471). For the overall cohort, the in-hospital mortality for patients with ischemic-hypoxic, metabolic, mixed, or unclassified phenotypes was 33.9% (95% confidence interval, 0.3–0.37), 28.4% (0.26–0.31), 41.5% (0.37–0.46), and 14.2% (0.12–0.16), respectively. In the multivariable logistic analysis, the mixed phenotype was associated with the highest risk of in-hospital mortality after adjusting for age, sex, GCS, and modified Sequential Organ Failure Assessment score (adjusted odds ratio, 2.11; 95% confidence interval, 1.67–2.67; P < 0.001). Conclusions: Four SAE phenotypes had different clinical outcomes. The mixed phenotype had the worst outcomes. Further understanding of these phenotypes in sepsis may improve trial design and targeted SAE management.