Functional outcome in patients with postanoxic encephalopathy after cardiac arrest (CA) often remains unclear, and there is a strong need of new prognostication measures. We aimed at investigating serum neurofilament light (NfL) chain concentration in patients with a postanoxic encephalopathy after CA and its prognostic potential. Serum samples were prospectively collected at different time points after CA in consecutive patients admitted to the intensive care unit (ICU) of Ticino Cardiocentre (Lugano, Switzerland) between June 2017 and March 2018. Serum NfL concentration was measured using a single molecule array (SIMOA) assay. The association of NfL levels with time to return of spontaneous circulation (ROSC), serum neuronal specific enolase (NSE) concentration, time between CA and sample collection, electroencephalogram (EEG) pattern and clinical outcome (death status at one month) were explored. Fourteen patients experiencing 15 CAs were included in the study (median age = 58 (57-68) years, 8 males). Median serum NfL concentration was 1027.0 (25.5-6033.7) pg/ml. There were positive associations between serum NfL and time to ROSC (rho = 0.60, p < 0.0001), NSE concentration (rho = 0.76, p < 0.0001), and severity of brain damage as estimated by EEG, with the highest concentrations measured in patients with suppressed electrical activity (14,954.0 [9006.0-25,364.0] pg/ml). Neurofilament light concentration remained high in samples collected up to 17 days after CA. Median NfL levels were higher among dead than alive patients at one month (6401.7 [3768.5-15,573.3] vs 25.5 [25.2-75.4] pg/ml). High NfL levels performed better than NSE in predicting death status at one month (NfL area under the curve (AUC) = 0.98, 95% confidence interval (CI) = 0.94-1.00; NSE AUC = 0.80, 95% CI = 0.67-0.94). These results support the potential inclusion of serum NfL in the battery of prognostication measures to be used in patients with postanoxic encephalopathy in ICU settings. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".