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Background: the role of smoking on clinical outcomes of central nervous system (CNS) inflammatory disorders is unclear. To assess the effect of smoking on relapses and disability in neuromyelitis optica with aquaporin-4-antibodies (NMOSD-AQP4-Ab), Myelin Oligodendrocyte Glycoprotein-antibodies associated disease (MOGAD) and relapsing remitting Multiple Sclerosis (MS) patients., Methods: in a UK cohort of 101 NMOSD-AQP4-Ab, 70 MOGAD and 159 MS, and a Korean cohort of 97 NMOSD-AQ4-Ab, time to first relapse, annualised relapse rate, onset relapse severity and recovery, time to Expanded Disability Status Score(EDSS)/secondary progressive MS (SPMS) were compared between never-smokers and ever-smokers. All clinical data were collected under the local ethics between January 2017 and January 2019., Results: Smoking did not affect the risk of relapse in any of the diseases. The risk of reaching EDSS 6.0 in the UK NMOSD-AQP4-Ab cohort was higher in ever smokers but this did not achieve significance (HR 2.12, p=0.068). When combining the UK and Korea NMOSD-AQP4-Ab cohorts, poorer recovery from the onset attack was significantly more frequent in the ever-smokers versus the never smokers (55% vs 38%, p=0.04). In the MS cohort the risk of reaching EDSS 6 and SPMS was significantly higher in the ever-smokers (HR=2.67, p=0.01 and HR=3.18, p=0.001). In MOGAD similar patterns were seen without reaching significance., Conclusions: In NMOSD-AQP4-Ab smoking associates with worse disability not through an increased risk of relapses but through poor relapse recovery. As in MS, smoking cessation should be encouraged in NMOSD-AQP4-Ab., (Copyright © 2021 Elsevier B.V. All rights reserved.)