ObjectiveTo determine the clinical feasibility of novel serum biomarkers in out-of-hospital cardiac arrest (OHCA) patients treated with target temperature management (TTM).MethodsThis study was a prospective observational study conducted on OHCA patients who underwent TTM. We measured conventional biomarkers, neuron‑specific enolase and S100 calcium-binding protein (S-100B), as well as novel biomarkers, including tau protein, neurofilament light chain (NFL), glial fibrillary acidic protein (GFAP), and ubiquitin C-terminal hydrolase-L1 (UCH-L1), at 0, 24, 48, and 72 h after the return of spontaneous circulation identified by SIMOA immunoassay. The primary outcome was poor neurological outcome at 6 months after OHCA.ResultsA total of 100 patients were included in this study from August 2018 to May 2020. Among the included patients, 46 patients had good neurologic outcomes at 6 months after OHCA. All conventional and novel serum biomarkers had the ability to discriminate between the good and poor neurological outcome groups (p < 0.001). The area under the curves of the novel serum biomarkers were highest at 72 h after cardiac arrest (CA) (0.906 for Tau, 0.946 for NFL, 0.875 for GFAP, and 0.935 for UCH-L1). The NFL at 72 h after CA had the highest sensitivity (77.1%, 95% CI 59.9–89.6) in predicting poor neurological outcomes while maintaining 100% specificity.ConclusionNovel serum biomarkers reliably predicted poor neurological outcomes for patients with OHCA treated with TTM when life-sustaining therapy was not withdrawn. Cutoffs from two large existing studies (TTM and COMACARE substudy) were externally validated in our study. The predictive power of the novel biomarkers was the highest at 72 h after CA.