Fatigue in multiple sclerosis is a frequent and disabling symptom that can interfere in daily functioning. The aim of this study is to demonstrate the relationship between fatigue and disability, disease course, depression and quality of life. We administered French valid versions of the Fatigue Impact Scale (EMIF-SEP), the short form of the Beck depression inventory (13 items) and the SF-36 to 237 out of 312 patients with clinically definite multiple sclerosis with EDSS<or=6.5. The EMIF-SEP is composed of four dimensions (cognitive, physical, social role and psychological) and allows a multidimensional evaluation. Using a multivariate analysis, EMIF-SEP total scores with physical and social role subscales were highly correlated with EDSS (p < 0.0001). Cognitive and psychological dimensions of the EMIF-SEP were not linked to EDSS. EMIF-SEP was not correlated with disease course after adjusting for EDSS. EMIF-SEP scores were significantly associated with depression scores (r = 0.74, p < 0.0001). The multivariate analysis also showed a significant impact of fatigue on each scale of quality of life of the SF-36. These data confirm that fatigue is correlated with disability, but cognitive and psychological dimensions of fatigue remain independent. Fatigue is also associated with depression and quality of life.