In patients with multiple sclerosis (MS), cognitive dysfunction particularly slowed cognitive processing speed (CPS), was a key source of disability. Compared to intramuscular interferon (IFN) Beta-1a, the sphingosine 1-phosphate receptor 1 and 5 modulator ozanimod reduced plasma neurofilament light chain concentration (pNfL, a marker of neurodegeneration) and improved CPS on the Symbol Digit Modalities Test (SDMT) in the phase 3 SUNBEAM trial. The post hoc study determined the link between pNfL concentration and SDMT scores at baseline and after ozanimod administration in SUNBEAM. Patients with relapse MS were randomized to once-daily oral ozanimod 0.92 or 0.46 mg (equivalent to ozanimod HCl 1 or 0.5 mg) or more than or equal to 12 months intramuscular IFN Beta-1a 30 µg in the double-blind, double-dummy SUNBEAM study. At baseline and 12 months, pNfL (as determined by Simoa technology) and SDMT (as part of a secondary outcome) were measured. Kendall’s correlation was used to assess baseline relationships between pNfL and SDMT, and linear regression and treatment-stratified bootstrap sampling were used to assess changes after treatment. About 1,346 people (mean [SD] age 35.6 [9.3] years; time since symptom start 7.0 [6.2] years; Expanded Disability Status Scale 2.6 [1.1]) took part in SUNBEAM: 447 received 0.92 mg ozanimod, 451 ozanimod 0.46 mg , and 448 IFN Beta-1a. The SDMT score was 48.0 (38.0, 56.0) and the median (IQR) pNfL was 14.7 (10.2, 23.3) pg/mL at baseline; Kendall’s correlation (95% CI) between these variables was -0.10 (-0.14 to -0.06), indicating a slight negative connection. Based on 1000 bootstrap samples, a greater median percent reduction in pNfL was associated with a greater mean SDMT change from baseline at month 12; both ozanimod doses were associated with greater median pNfL reductions and mean SDMT improvements than IFN Beta-1a, with 0.92 mg showing the greatest differences from IFN Beta-1a. There were no links between baseline pNfL and any SDMT category (worsened/stable/improved based on a ≥4-point shift from baseline at month 12). Baseline pNfL linked inversely with baseline SDMT in an exploratory post hoc analysis of the SUNBEAM experiment. Ozanimod treatment reduced pNfL and improved SDMT more than IFN-1a treatment. To assess the clinical efficacy of pNfL as a CPS marker, more prospective studies were needed.