Sepsis-associated encephalopathy (SAE), the state of altered mentation (AMS) as a result of infection is a poorly understood yet common ED presentation that may have long-term implications. To date, there have been no contemporary serum biomarker available for the diagnosis, management, or prognosis of AMS in SAE. We investigated the diagnostic and prognostic utility of six neural biomarkers (glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCHL1), S100 calcium-binding protein B (S100B), Tau protein, Neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH)) to assess their role in predicting cognitive performance and outcomes in ED sepsis. A single center, prospective, longitudinal study of ED patients > 18 years with suspected or confirmed infection and systemic inflammatory response syndrome criteria was performed. Those with a history of neurologic, chronic liver or kidney disease were excluded. AMS was defined a priori by the clinician and serial serum collection for biomarker analysis was performed 0, 6, 12, 18, 24, 48, and 72 hours after enrollment. Subjects were enrolled within 6 hours of ED arrival. Outcomes included cerebral performance category (CPC) and mortality at 6-months. Associations between sepsis patients with and without AMS and outcomes were tested by Fisher’s exact test and Mann-Whitney U-test. Receiver operator characteristics curves were created to evaluate the utility of biomarker concentrations or change in biomarkers concentrations in the diagnosis of SAE and prognosis of outcomes. Potential cutoff points were defined by the Youden’s J statistic. Of the 23 sepsis patients recruited, 11 (47.8%) and 12 (52.2%) presented with and without AMS, respectively. The mean age of the AMS cohort was 70.3 years (95% CI 58-82), versus the non-AMS 51.7 years (95% CI 40-63) (p=0.023). There was no difference in sex, race, ethnicity, or APACHE II score at baseline observed. Of the biomarker concentrations or change in concentrations analyzed at the defined study collection time points, 19, 17, and 16 unique measures demonstrated discriminatory utility in the diagnosis of SAE and the identification of outcomes. The concentration ratio between GFAP/UCHL1 at baseline demonstrates the best utility in diagnosing SAE with an AUC of 0.93 (95% CI .83-.99). The concentration ratio between GFAP/S100b, UCHL1/pNFH, Tau/S100b, and S100b/pNFH at 72 hours demonstrated complete discriminatory utility in prognosticating neurological performance at hospital discharge and mortality at 6 months. In this pilot, S100B, pNFH, GFAP, UCHL1, Tau, and NFL were able to discriminate between subjects demonstrating diagnosed acute SAE, and therefore can be useful to determine the prognosis for persistent cognitive dysfunction and long-term survival among sepsis patients. Biomarker cut points have been further identified to inform clinicians as to whether the subject’s biomarker levels are abnormal.