Although different factors are probably involved in the etiology of fatigue in multiple sclerosis patients, no definite mechanism has been proposed. We have proposed that fatigue is a complex symptom that includes three clinical different entities (asthenia, fatigability and worsening of symptoms with effort). The goal of this study is to demonstrate if there is a peculiar mechanism for each of the different varieties of fatigue. A control sample of 155 patients (105 women, 50 men) with clinically definite MS was studied. Fatigue was measured using the Fatigue Descriptive Scale (FDS) and the Fatigue Severity Scale (FSS). Treatment, depression, anxiety, sleep and cellular immune status were studied too. Fatigue was a symptom in 118 patients (76.13%); 26 patients (22.03%) described it as asthenia (fatigue at rest); 85 patients (72.03%) as fatigability (fatigue with exercise), and seven patients (5.9%) as worsening of symptoms. The severity of pyramidal involvement was significantly more severe in patients suffering from fatigue; some immunological parameters were associated with fatigue as well. The discriminant analysis of the data shows that some of the immunoactivation parameters are associated with asthenia (F=21.5, P<0.001), and pyramidal tract involvement is associated with fatigability (F=10.5, P<0.001). Sleep disorders, anxiety and depression were linked with fatigue in a few patients. No relationship with treatment was proven. In conclusion, fatigue in MS seems to be a heterogeneous entity. Asthenia and fatigability may be different clinical entities. Certain immunoactivation parameters correlate with the presence of asthenia while pyramidal involvement is associated with fatigability.