Background:Symptoms of anxiety, depression and fatigue are common comorbidities among persons with multiple sclerosis (PwMS). A previous pilot study supported Pilates as a feasible exercise modality that may improve these outcomes among PwMS.Objective:To quantify the effects of 8 weeks of home-based Pilates on symptoms of anxiety, depression and fatigue among PwMS.Methods:A total of 80 PwMS (69 female) were randomized to twice-weekly home-based Pilates guided by a DVD) or wait-list control. Validated questionnaires assessed anxiety, depressive and fatigue symptoms at baseline, weeks 2, 4, 6 and 8. Using intention to treat, repeated measures analysis of covariance (RM-ANCOVA) adjusted for baseline physical activity examined between-group differences across time. Hedges' d quantified the magnitude of differences in outcome change. Sensitivity analyses examined female-only samples.Results:Group x time interactions were statistically significant for all outcomes (all p <= 0.005). Pilates significantly reduced (all p <= 0.03) depressive symptoms (Quick Inventory of Depressive Symptomatology, d = 0.70; Hospital Anxiety and Depression Scale-Depression, d = 0.74), anxiety (State-Trait Anxiety Inventory, d = 0.30; Hospital Anxiety and Depression Scale-Anxiety, d = 0.49), cognitive (d = 0.44), physical (d = 0.78), psychosocial (d = 0.56) and total fatigue (d = 0.76). Female-only results were materially the same.Conclusion:Home-based Pilates significantly improved anxiety, depressive and fatigue symptoms among PwMS with minimal-to-mild mobility disability, including moderate-to-large, clinically meaningful improvements in depressive and fatigue symptoms.Trial Registration: ClinicalTrials.gov (NCT04120207)