BACKGROUND: Health-related quality of life (HRQoL) is impaired in multiple sclerosis (MS) but can be improved by disease-modifying therapies such as natalizumab. However, the predictive factors and neuropsychiatric correlates of HRQoL improvement are unknown. METHODS: In this study, 48 patients with relapsing-remitting MS were included in a 3-year open-label, single group, multicenter, clinical trial (NCT01392872). HRQoL was measured by the disease-specific MusiQoL questionnaire, together with physical disability, cognition, fatigue, anxiety and depression scores at baseline, 6months, 12months, 18months and 36months after starting natalizumab therapy. RESULTS: Compared to baseline, global HRQoL, as measured with the index of the MusiQoL, was significantly increased 6months after the beginning of natalizumab therapy, with medium effect-size (58.6+/-16.2 vs 69.8+/-18.9, p<0.001, Cohen's d=0.63). This improvement was maintained over time for up to 3years and mainly concerned activity of daily living, psychological well-being, symptoms and coping (p<0.001 for every dimensions). The variation of global HRQoL after 3years was negatively correlated with the variation of fatigue score (r=-0.44, p=0.015). Furthermore, a higher fatigue score at baseline was correlated with improvement in global HRQoL 3years afterwards (r=0.34, p=0.041), independently of age, educational level, disease duration and disability at baseline (beta=2.45, p=0.020). Disability at baseline, cognitive impairment, anxiety and depression failed to predict or correlate with global HRQoL improvement in multivariate analyses. CONCLUSION: Natalizumab improved HRQoL quickly and sustainably in patients with relapsing-remitting MS. In terms of HRQoL, natalizumab seems to benefit mostly patients with more marked fatigue at baseline.