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OBJECTIVE: To assess multiple sclerosis (MS) associated fatigue after the first 6 months of natalizumab treatment. METHODS: Prospective, open-label, uncontrolled study. Fatigue was measured before treatment initiation and at month 6 with the Modified Fatigue Impact Scale (MFIS) and the Fatigue Severity Scale (FSS) in 42 patients. Subjective impression of well-being was assessed with a visual analogue scale (1-10). RESULTS: 42 patients were followed (mean age 35.1 years, 60% female, mean EDSS 3.7). The mean total MFIS were 45.8 (17.5) at baseline and decreased to 40.1 (18.0) (p<0.01) at month 6. Mean scores on the VAS for subjective impression of well-being increased from 5.5 (1.9) to 6.1 (2.1) at month 6 (p<0.01). Pre-treatment annual relapse rate decreased from 2.2 to 0.2, gadolinium enhancing lesions were reduced by 96% with natalizumab. There was no correlation of gadolineum enhancing lesions and fatigue scores. CONCLUSION: Fatigue and well-being improved after treatment initiation with natalizumab. A randomized controlled trial is necessary to come to definite conclusions as to a potential effect of natalizumab on fatigue in MS.