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Aim: We evaluated serum tau protein as biomarker for poor neurological outcome over an extended observation period in patients after successful cardiopulmonary resuscitation (CPR) treated with mild therapeutic hypothermia (MTH) or normothermia (NT)., Methods: This is a retrospective analysis of a prospective observational study including 132 patients after successful CPR. Serum tau was determined in 24 h intervals for up to 168 h after CPR. Patients were treated with MTH targeting a temperature of 33 °C for 24 h or NT according to current guidelines. Neurological outcome was assessed with the Cerebral Performance Categories Scale (CPC) at hospital discharge., Results: Forty-three percent of the patients were treated with MTH. Serial serum tau levels (pg/ml) showed a peak between 72-96 h after CPR (159 (IQR 27-625). Patients with poor neurological outcome (CPC 3-5) at hospital discharge (n = 68) had significantly higher serum tau levels compared to patients with good neurological outcome at 0-24 h (164 (48-946) vs. 69 (12-224); p = 0.009), at 24-48 h (414 (124-1049) vs. 74 (0-215); p < 0.001), at 48-72 h (456 (94-1225) vs. 69 (0-215); p < 0.001) and at 72-96 h (691 (197-1173) vs. 73 (0-170); p < 0.001). At 72-96 h the AUC to predict poor neurological outcome was 0.848 (95% CI: 0.737-0.959). Serum tau levels were not significantly different between patients with MTH and NT in multivariate analysis after adjusting for clinical relevant covariates., Conclusion: Serum tau showed highest values and the best prognostic discrimination of poor neurological outcome at 72-96 h after CPR. Prolonged elevation may indicate ongoing axonal damage in patients with hypoxic encephalopathy., (Copyright © 2020. Published by Elsevier B.V.)