Fatigue, a common complaint among patients with multiple sclerosis (MS), is poorly characterized. We developed a computerized method that quantitatively measures fatigue, and defined a fatigue index (FI), which is the ratio between the integral of muscle strength decay over time and maximal voluntary contraction. Thirty patients (mean age, 37.4 ± 10.3 years) were examined-20 patients with pyramidal tract involvement and 10 patients with involvement of other neurologic systems. We evaluated 10 patients during relapse and 3 months afterwards, and compared their results with those of four patients with chronic fatigue syndrome (CFS) and 13 age-matched healthy subjects. The FI was significantly higher in the MS patients as compared with the CFS patients and normal controls: 34.2 ± 6.4% versus 27.5 ± 1.0% and 23.6 ± 6.8%, p < 0.05. Within the MS group, the FI correlated with the presence of pyramidal signs-43.5% compared with 33% in patients without pyramidal signs, p < 0.01. In MS patients, fatigue worsened during a relapse affecting the pyramidal tract, but not during a relapse in other systems. These results demonstrate that fatigue can be quantitatively measured in MS patients, and that pyramidal dysfunction leads to increased fatigability.