Background: Sensory vincristine-related neuropathy is a well-known toxicity of front-line lymphoma treatments, potentially negatively impacting both disease outcomes as well as the long-term quality of life of cancer survivors. Most aggressive non-Hodgkin lymphomas are curable with the multi-agent chemotherapy regimens CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or infusional dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin). This pilot study aimed to characterize and describe chemotherapy-induced peripheral neuropathy (CIPN) outcomes, utilizing patient and clinician-reported outcome measures and neurofilament light chains (NF-L). Nf-L, released in response to axonal damage, is emerging as a sensitive blood-based biomarker for CIPN. Studies in rats have demonstrated repeated vincristine exposure correlated with increased serum NF-L light chains and progressive damage. This has not previously been reported in humans. Methods: A single-center prospective study assessed CIPN toxicity in people with aggressive non-Hodgkin’s lymphoma treated with CHOP and EPOCH. Patient-reported outcome (PRO) measures included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy Induced Peripheral Neuropathy (EORTC QLQ-CIPN20) questionnaire. Items 19 and 20 were excluded. The clinician-reported outcome measure was the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v5.0). Outcomes were evaluated at three time points: (1) Baseline, (2) Immediately before cycle four, and (3) Immediately before cycle six. Blood samples were collected from participants and processed for plasma Nf-L chain analysis. Results: There were 26 participants at baseline (CHOP: n = 17, EPOCH: n = 9), 21 participants at time point 2 (CHOP: n = 17, EPOCH: n = 7), and 16 participants at time point 3 (CHOP: n = 10, EPOCH n = 6). The mean CIPN-18 scores increased at each time point and were not significantly different by chemotherapy type. Five of the 16 participants (31.3%) experienced CIPN ≥ grade 1 at time point 3. A significant relationship existed between the CIPN-18 and the CTCAE (r- 0.39, p =0.002) and between CIPN-18 and Nf-L levels (r= 0.42, p = 0.002). The mean Nf-L levels increased from the first time point (mean = 54.4 pg/mL, 16-187.9 pg/mL) to the second time point (mean = 108.7 pg/mL, 37-232.2 pg/mL) and remained significantly elevated at Time Point 3 (mean = 92pg/mL, 34-172.2 pg/mL). Conclusions: One-third of all participants were experiencing symptoms of CIPN by the third time point (cycle six of therapy), as measured by the CTCAE > 0 and the CIPN-18 > 20. Our study lays the groundwork for using Nf-L as a potential biomarker, in combination with PROs, to identify, recognize, and measure vincristine-induced neurotoxicity.