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The Work Ability in Natalizumab-Treated MS Patients (WANT) study assessed work ability, quality of life, and cognitive processing speed during natalizumab treatment. WANT was a 1-year, prospective, multicenter observational study conducted in Italy. Inclusion criteria included relapsing-remitting multiple sclerosis (MS), natalizumab treatment, full-time worker status, and loss of working hours due to MS as measured by the Work Productivity and Activity Impairment Questionnaire for MS (WPAI:MS). The primary endpoint was change in WPAI:MS domain scores after 1 year on natalizumab. Secondary endpoints included change in annualized relapse rate (ARR), Multiple Sclerosis Impact Scale (MSIS-29) score, and Symbol Digit Modalities Test (SDMT) score. At enrollment, the 91 patients had a mean age of 38.3 (standard deviation [SD], 9.0) years and a mean ARR of 1.5 (SD, 0.8). After 1 year, improvements were observed in all WPAI:MS domains, with significant reductions in Absenteeism (−4.2 [SD, 26.0], p = 0.0190) and Work Productivity Loss (−7.2 [SD, 28.6]; p = 0.0456). These changes were accompanied by a low ARR (0.1), and 87.9% of patients were relapse free. Significant improvement was observed in MSIS-29 physical and psychological domains (reductions of 2.8 [SD, 11.6; p = 0.0295] and 6.3 [SD, 15.6; p = 0.0007], respectively) and SDMT score (increase of 2.4 [SD, 7.9; p = 0.0006]). Adverse events were reported in 32 of 104 patients (30.8%). The reductions in Absenteeism and Work Productivity Loss and the improved physical and psychological functioning reported after 1 year of natalizumab treatment in real-world settings extend our understanding of natalizumab’s effects on patient-centric and health economics outcomes.