BackgroundWe analysed the COMparison Between All immunoTherapies for Multiple Sclerosis (NCT03193866), a Swedish nationwide observational study in relapsing–remitting multiple sclerosis (RRMS), to identify trajectories of fatigue and their association with physical disability following start of disease-modifying therapy (DMT).MethodsUsing a group-modelling approach, we assessed trajectories of fatigue with the Fatigue Scale for Motor and Cognitive Functions and physical disability with Expanded Disability Status Scale among 1587 and 1818 individuals who initiated a first DMT and had a first DMT switch, respectively, followed during 2011–2022. We investigated predictors of fatigue trajectories using group membership as a multinomial outcome and calculated conditional probabilities linking membership across the trajectories.ResultsWe identified five trajectories of fatigue in participants who initiated their first DMT: no fatigue (mean starting values=23.7; 18.2% of population), low (35.5; 23.9%), mild (49.0; 21.6%), moderate (61.3; 20.1%) and severe (78.7; 16.1%). While no, low, mild and severe fatigue trajectories remained stable, the moderate trajectory increased to severe fatigue. Similarly, we identified six fatigue trajectories among participants who did a DMT switch, all indicating stable values over time. Women initiating a first DMT were more likely than men to display a severe fatigue trajectory, relative to the no fatigue one. There was a strong association between fatigue and physical disability trajectories.ConclusionsIn this cohort of people with actively treated RRMS, self-reported fatigue remained stable or increased over the years following DMT start. There was a strong association between fatigue and disability after DMT start.