Abstract: OBJECTIVE To explore the value of angiopoietin-2(ANGPT2) combined with S100 calcium-binding protein β (S100β) in prediction of poor prognosis of the patients with sepsis-associated encephalopathy (SAE) so as to provide bases for assessment of prognosis of the SAE patients. METHODS A total of 292 patients with SAE who were treated in critical care medicine department of The Affiliated Hospital of Xuzhou Medical University from Jan. 2023 to Jan. 2025 were recruited as the research subjects and were divided into the survival group with 230 cases and the death group with 62 cases according to the 28-day prognosis. The baseline data (including age, sex, complications), infection sties, Sequential Organ Failure Assessment (SOFA) score, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, and levels of serum ANGPT2 and S100β were observed and compared between the two groups of patients. The efficiencies of ANGPT2, S100β and their combination in prediction of poor prognosis of the SAE patients were evaluated by means of receiver operating characteristic (ROC) curves and the area under the curve (AUC). RESULTS There were significant differences in the age 58.32(48.06,69.27) years old vs. 52.57 (40.49,60.66) years old, SOFA score12.00 (11.00,15.00) points vs. 10.00 (9.00,12.00) points , APACHE II score16.00(8.00,24.00) points vs. 9.00(5.00,12.00) points , serum S100β170.00(140.00,210.00)pg/ml vs. 140.00(110.00,150.00)pg/mland serum ANGPT229.00(25.00,34.00)ng/ml vs. 14.00(12.00,15.00)ng/mlbetween the death group and the survival group(P＜0.05). ROC curve analysis showed that ANGPT2 combined with S100β showed the optimal prediction efficiency for the prognosis of the SAE patients, with the AUC 0.942(95%CI:0.908 to 0.976), the sensitivity 0.935, the specificity 0.913. CONCLUSION The serum ANGPT2 combined with S100β has high efficiency in prediction of the poor prognosis of the SAE patients and has significant value in clinical application as well.