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Fatigue is one of the most debilitating symptoms in multiple sclerosis (MS). The aim of this study was to observe the severity of MS associated fatigue in a community-based sample of natalizumab (ntz) treated patients over one year. In 48 relapsing remitting MS patients (mean age=38.3 years) fatigue was longitudinally measured with the Modified Fatigue Impact Scale (MFIS) at two time points. The primary analysis of differences in MFIS was performed using non-parametric Wilcoxon test for dependent variables. Mean total MFIS Score increased significantly from 32.6±20.9 to 49.1±20.0 over the observation period of 12 months (p<0.001). 83% of patients remained clinically disease activity free (no relapse, no progression in the Expanded Disability Status Scale, EDSS) over the observation period of one year. Age, gender, disease duration, spinal involvement, Gd-enhancement, depressive symptoms and EDSS had no influence on fatigue levels as measured with MFIS. Severity of fatigue symptoms during ntz treatment might increase despite very low disease activity.