Objectives: We aimed to determine if elevations in serum neuron-specific enolase are associated with brain injury and outcomes in adults who require venoarterial extracorporeal membrane oxygenation. Design: Prospective observational study. Setting: Two ICUs of a university hospital, Paris, France. Patients: Consecutive adult patients treated with venoarterial extracorporeal membrane oxygenation for refractory cardiogenic shock or in-hospital refractory cardiac arrest. Interventions: None. Measurements and Main Results: Serum sampled 1, 3, and 7 days after venoarterial extracorporeal membrane oxygenation cannulation was stored at –80°C and neuron-specific enolase concentrations were measured in batches at the end of the study. The association between neuron-specific enolase concentrations and outcomes (28-d mortality and poor outcome, defined by a score of 4–6 on the modified Rankin scale at 90 d) were explored by multivariable logistic regression, with neuron-specific enolase concentrations dichotomized according to median values. One-hundred three patients were included, of whom 26 (25%) received preextracorporeal membrane oxygenation cardiopulmonary resuscitation. Median (interquartile range) day-1, day-3, and day-7 neuron-specific enolase serum concentrations were 37 μg/L (26–51 μg/L), 25 μg/L (19–37) μg/L, and 22 μg/L (17–31 μg/L). After adjustment for Simplified Acute Physiology Score II, preextracorporeal membrane oxygenation cardiopulmonary resuscitation, and Sepsis Organ Failure Assessment score at time of cannulation, a day-3 neuron-specific enolase greater than 25 μg/L remained independently associated with 28-day mortality (adjusted odds ratio, 4.98; 95% CI, 1.86–13.32) and poor outcome at 90 days (adjusted odds ratio, 4.63; 95% CI, 1.81–11.84). A day-3 neuron-specific enolase threshold greater than 80 μg/L had a 100% specificity for prediction of both mortality (95% CI, 92–100%) and poor functional outcome (95% CI, 89–100%). In a subset of patients who underwent brain CT, neuron-specific enolase concentrations were significantly higher in patients diagnosed with stroke, as compared with those without stroke. Conclusions: In adult patients under venoarterial extracorporeal membrane oxygenation, day-3 serum neuron-specific enolase concentrations are independently associated with short-term mortality and poor functional outcomes. These findings deserve validation in a multicenter setting.