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Introduction Chemotherapy-induced peripheral neuropathy (CIPN) is a potentially disabling complication of the neurotoxic chemotherapies; however, its occurrence is often unpredictable. We aimed to determine whether serum levels of neurofilament light chain (sNfL) could predict the onset and severity of CIPN, and whether sNfL levels were associated with other clinical factors in people with cancer.Methods Adult patients (>18 years) prescribed at least four cycles of oxaliplatin, cisplatin, docetaxel or paclitaxel were clinically assessed and had blood taken for sNfL analysis at baseline and prior to each cycle. Peak sNfL was compared with clinical characteristics and Total Neuropathy Score-Clinical version (TNSc), National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, V.4.03) and CIPN-Rasch-built Overall Disability Scale (CIPN-RODS). Individual patient trends in sNfL and TNSc were examined.Results 42 patients completed the study, with 36 receiving platinum agents and 6 receiving taxanes. Peak sNfL was higher with taxanes than with platinum agents (129.9 vs 31.0 pg/mL; p<0.0001). Higher peak sNfL was not associated with final TNSc, CTCAE or CIPN-RODS in patients receiving platinum agents. Using age-adjusted NfL z-scores, peak sNfL was associated with CIPN-RODS (rs=−0.45; p=0.012) and was higher in patients with a final CTCAE Grade of 2 compared with Grades 0–1 (p=0.015) but was not associated with final TNSc (rs=+0.37, p=0.050). In patients receiving platinum agents, higher peak sNfL was associated with death within 6 months of study entry (p=0.020). sNfL rose in conjunction with the increase in TNSc but did not precede clinical symptoms/signs of neuropathy in most patients.Conclusion Taxanes cause greater and sharper sNfL rises than platinum agents. Age-adjusted sNfL associates with neuropathy severity in platinum-treated patients; however, in most patients it is unable to detect early axonal damage before this is detectable with clinical examination.