Neurological side effects after chimeric antigen receptor-modified (CAR) T cell therapy are common and potentially devastating. Termed immune effector cell-associated neurotoxicity syndrome (ICANS), symptoms range from mild encephalopathy to diffuse cerebral edema. No predictive biomarkers exist to identify individuals at risk for developing ICANS. Serum neurofilament light chain (NfL) is a well-established marker of neural injury known to dynamically change in neuro-inflammatory disorders (e.g. multiple sclerosis). We hypothesized individuals undergoing CAR T cell therapy who ultimately developed ICANS would have early and sustained elevations in serum NfL. We performed a retrospective analysis of serum samples from 11 individuals treated with tisagenlecleucel or axicabtagene ciloleucel (mean age 61.3, 18% female, 27% ICANS, all with peak severity score 3). Most individuals had a longitudinal sampling at baseline, pre-infusion, post-transfusion day (PTD) 1, PTD 3, PTD 7, PTD 14, and PTD 30. Serum NfL were assayed using a Simoa HD-1/HD-X kit (QuanterixTM). We found that individuals who developed ICANS had early and sustained elevations in serum NfL levels at baseline (p = 0.0075), pre-infusion (p = 0.0172), and PTD 3 (p = 0.0026) and PTD 30 (p = 0.0066). All group comparisons survived multiple comparison testing using false-discovery rate (FDR). Receiver operating characteristic (ROC) curve classification by logistic regression of serum NfL revealed an area under the curve (AUC) of 1.0 with a cut-off of 44 pg/mL. No correlation was observed between NfL levels and age, sex, or history of central nervous system involvement of the underlying malignancy. In summary, we found serum NfL levels are a robust, early marker for the development of ICANS. Our findings suggest the risk of developing ICANS reflects pre-transfusion host-factors, permitting the screening well in advance of drug administration.