Introduction: Neuron Specific Enolase (NSE) and astroglial protein S-100b have been proposed as serum biomarkers to predict outcome following resuscitation from cardiac arrest. Hypothesis: We hypothesize that NSE and S-100b levels are associated with depth of coma on hospital arrival and are associated with survival to hospital discharge. Methods: Prospective cohort of subjects successfully resuscitated from cardiac arrest. Levels of NSE and S-100b were obtained at arrival and 24 hours after cardiac arrest. The change in these levels was determined. Data included demographic information, category of post-cardiac arrest illness severity ((I) awake, (II) coma (not following commands but intact brainstem responses) + mild cardiopulmonary dysfunction (SOFA [Sequential Organ FailureAssessment] cardiac + respiratory score <4), (III) coma + moderate-severe cardiopulmonary dysfunction (SOFA cardiac + respiratory score >=4), and (IV)coma without brainstem reflexes) and survival to hospital discharge. Non-normal data were log-transformed. Levels of NSE and S-100b at each time interval were compared by category of post-cardiac arrest illness severity using ANOVA. Single variable logistic regression was used to determine predictors of survival using a cut-off of p<0.1. Multivariable logistic regression was used to create a final parsimonious model. Hosmer-Lemeshow value was used to determine goodness of fit. Results: Of 86 subjects, 9 were awake and excluded. Mean age was 59 (SD 16) years and most were male (N=44, 57%). Out of hospital cardiac arrest made up 69% (N=53), with VF/VT and PEA the majority of rhythm at arrest (47% and 25%). Most (N=71, 93%) received TH. Grouped by arrest categories: category II comprised 30 (39%); category III, 15 (19%), and category IV, 32 (42%). Survival was 39% (N=30). Category IV illness severity was associated with higher levels of NSE at 24 hours (1.22, SD=0.51;1.03, SD=0.53; 1.63, SD=0.35; p=0.001). Category IV illness severity was associated with higher levels of s100b at arrival (-0.83, SD=0.75) and 24 hours (-0.92, SD=0.78). In the multivariate analysis, only change in NSE between arrival and 24 hours was associated with survival (OR=0.96, CI: 0.92 - 0.99). Category II illness severity (OR=1.64, CI: 0.30 - 9.05) Category IV illness severity (OR=0.30, CI: 0.05 – 1.86) and VF (OR=2.46, CI: 0.62-9.81) were not associated with survival. Conclusions: More severe neurologic injury on initial examination is associated with higher levels of NSE and S-100b 24 hours following resuscitation. The change in NSE between arrival and 24 hours after resuscitation is associated with survival.