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Background: Multiple sclerosis (MS) is characterized by extensive tissue damage leading to a range of complex symptoms, including physical disability and cognitive dysfunction. Recent work has indicated the clinical relevance of bioactive lipid mediators (LMs), which are known to orchestrate inflammation and its resolution and are deregulated in MS. However, it is unknown whether LM profiles relate to white matter (WM) damage., Objectives: To investigate the potential association between plasma-derived LMs and MRI-quantified WM damage using fractional anisotropy (FA) and grey matter (GM) atrophy in dimethyl fumarate-treated relapsing remitting MS (RRMS) patients., Methods: Severity of FA-based WM damage and GM atrophy was determined in RRMS patients (n = 28) compared to age- and sex-matched controls (n = 31) at treatment initiation (baseline) and after 6 months. Plasma LMs were assessed using HPLC-MS/MS and baseline LMs were correlated to changes in FA and brain volumes., Results: We observed significant WM damage in RRMS patients (mean age 41.4 [SD 9.1]) at baseline and follow-up (z-score=-0.33 and 0.31, respectively) compared to controls (mean age 41.9 [SD 9.5]; p < 0.001 for both comparisons). Patients with severe WM damage showed a decline of thalamic volume (p = 0.02), and this decline correlated (r = 0.51, p < 0.001) with lower baseline levels of 9-HODE. This LM also predicted FA worsening (beta = 0.14, p < 0.001) over time at 6 months., Conclusion: Despite the relatively small sample size, lower baseline levels of the LM 9-HODE correlated with more thalamic atrophy and predicted subsequent worsening of WM damage in RRMS patients., Competing Interests: Declaration of competing interest W.H. Fung: nothing to disclose; M.R. van Lingen was supported during this study by a research grant of Biogen and currently by MEGIN; J.Y. Broos: nothing to disclose; K.H. Lam: nothing to disclose; M. van Dam is supported by a research grant from BMS; W.K. Fung: nothing to disclose; S. Notenboom: nothing to disclose; I. Koubiyr: nothing to disclose; H.E. de Vries: nothing to disclose; B. Jasperse: nothing to disclose; C.E. Teunissen reports funding from National MS Society (Progressive MS alliance) and Innovative Medicines Initiatives 3TR (Horizon 2020, grant no 831,434). CET has a research contract with Celgene. She serves on editorial boards of Medidact Neurologie/Springer, Neurology: Neuroimmunology & Neuroinflammation, and is editor of a Neuromethods book Springer; M. Giera: nothing to disclose; J. Killestein received research grants for multicentre investigator initiated trials DOT-MS trial, ClinicalTrials. gov Identifier: NCT04260711 (ZonMW) and BLOOMS trial (ZonMW and Treatmeds), ClinicalTrials. gov Identifier: NCT05296161); received consulting fees for F. Hoffmann-La Roche, Biogen, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); reports speaker relationships with F. Hoffmann-La Roche, Biogen, Immunic, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); adjudication committee of MS clinical trial of Immunic (payments to institution only); H.E. Hulst is an editor of the Multiple Sclerosis Journal controversies sections, receives research support from the Dutch MS Research Foundation and the Dutch Research Council. She has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Novartis, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, MedDay and Merck BV; E.M.M. Strijbis serves on the editorial board of Frontiers in Neurology and receives research support from Stichting MS Research and ZonMW. She has received speaker fees from Merck and Novartis. M.M. Schoonheim serves on the editorial board of Neurology, Multiple Sclerosis Journal and Frontiers in Neurology, receives research support from the Dutch MS Research Foundation, Eurostars-EUREKA, ARSEP, Amsterdam Neuroscience, MAGNIMS and has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Celgene/Bristol Meyers Squibb, EIP, Sanofi, MedDay and Merck; Gijs Kooij received research support from Biogen, Novartis and Merck., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)