<p>COVID-19 is associated with encephalopathy, but its diagnosis and prognostic value has yet to be fully characterized. We aimed to examine key neurobiomarkers of encephalopathy in patients with severe COVID-19 pneumonia, specifically serum neuron-specific enolase (NSE), serum S100-beta protein (S100B), and early electroencephalographic (EEG) abnormalities, and their association with short-term outcomes. We conducted a prospective, single-center cohort study including consecutive adult patients with COVID-19 admitted to the intensive care unit (ICU) for acute respiratory failure. NSE and S100B levels were measured on days 1, 2, and 3 post-admission, and standard EEG was performed as part of routine neuromonitoring. The primary outcome was mortality at 90 days. Among 134 included patients, 47 (35.1%) died within 90 days. NSE concentrations on days 1, 2, and 3 were significantly associated with mortality and intubation, whereas S100B concentrations were not. In multivariable analyses, maximal NSE concentration between day 1 and day 3 (adjusted odds ratio (aOR) 1.15, 95% CI 1.06–1.24), absence of EEG sleep figures (aOR 14.28, 95% CI 2.38–76.92), age (aOR per 1-point 1.10, 95% CI 1.04–1.17), and SOFA score (aOR per 1-point 1.28, 95% CI 1.01–1.62) were independently associated with mortality. NSE predicted mortality with an area under the Receiver Operating Characteristic curve of 0.72 (95% CI 0.61–0.82). An NSE threshold &gt; 34microg/L predicted mortality with a specificity of 95% (95% CI 87–99%) and a sensitivity of 24% (95% CI 13–40%). Among patients with severe COVID-19 pneumonia, elevated serum NSE levels and absence of EEG sleep features, suggesting subclinical encephalopathy, were independently associated with increased mortality. These findings support the use of serum NSE and EEG as early prognostic biomarkers in critically ill patients without primary brain injury.</p>