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Objective: Particulate matter (PM) of aerodynamic diameter smaller than 10 μm (PM 10 ) has been associated with multiple sclerosis (MS) relapse. However, the impact of smaller PM with a greater ability to penetrate human organism has never been assessed. We evaluated the impact of PM smaller than 2.5 μm (PM 2.5 ) on the risk of MS relapse. Material and Methods: In a case-crossover study, we included 2,109 consecutive hospitalizations likely due to MS relapse in day hospital in 5 MS centers in the Paris area from January 2009 to December 2013. For each hospitalization, the natural logarithm of the average weekly PM 2.5 concentrations (μg/m 3 ) at the patient's residence address during each of the 6 weeks (week[0] to week[-5]) preceding admission was compared with the concentration during the previous week, using a conditional logistic regression adjusted on temperature, flu-like syndrome rate, pollen count, and holiday period. Results: PM 2.5 average concentration during week[-3] was significantly associated with the risk of hospitalization for MS relapse [OR = 1.21 (CI 1.01;1.46)]. The association was stronger in patients younger than 30 years [OR=1.77 (CI 1.10; 2.83)]. Conclusion: Our study demonstrates an association between exposure to PM 2.5 and MS relapse, particularly in young people., Competing Interests: EJ reports reimbursement for conference registration fees, travel expenses, and accommodation from Sanofi Genzyme, outside the submitted work. BS has received fees for advisory boards and lectures from Genzyme, Merck-Serono, Novartis, Teva, and Biogen, and research support from Roche, Genzyme, and Merck-Serono. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Januel, Dessimond, Colette, Annesi-Maesano and Stankoff.)