| Summary: | <i>Background and objectives</i>: Fatigue is one of the most disabling symptoms that limit daily life activities in persons with multiple sclerosis (pwMS). This study aimed to evaluate the effects of maximal strength training (MST) on perceived-fatigue and functional mobility in pwMS. <i>Materials and Methods</i>: 26 participants with MS were balanced according to their pre-intervention fatigue scores and distributed into an MST group (<i>n</i> = 13) and a control group (CG; <i>n</i> = 13). The MST group completed eight weeks using high loads, evaluating detraining after ten weeks. Quadriceps and hamstring isokinetic (QPT<sub>IK</sub>; HPT<sub>IK</sub>) and isometric (QPT<sub>IM</sub>; HPT<sub>IM</sub>) peak torques were assessed using an isokinetic dynamometer. Effect size differences were estimated with the Hedges’ <i>g</i> index (<i>d<sub>g</sub></i>). Fatigue was evaluated through the Fatigue Severity Scale (FSS), while functional mobility was assessed via the Timed Up and Go Test (TUG). <i>Results</i>: The MST significantly improved all the strength measurements after the intervention (Δ6.43–29.55%; <i>p</i> < 0.05) compared to the control group. FSS showed a significant reduction (59.97%, <i>d<sub>g</sub></i> = 5.41, large). The MST group also reduced the TUG time (19.69%; <i>d<sub>g</sub></i> = 0.93, large) compared to the control group. Improvements caused by the intervention did not remain after a 10-week follow-up, with decreases in strength performance from 4.40% to 13.86% (<i>d<sub>g</sub></i> = 0.24–0.56, small to moderate), 112.08% in the FSS (<i>d<sub>g</sub></i> = −3.88, large), and 16.93% in TUG (<i>d<sub>g</sub></i> = −1.07, large). <i>Conclusions</i>: MST (up to 90% 1RM) seems to be a feasible and useful way to obtain clinically relevant improvements in the perceived-fatigue symptoms and functional mobility. Still, symptom improvements decrease after a 10-week detraining period.
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