Fatigue is a prominent disabling symptom in a variety of medical and neurologic disorders. To facilitate research in this area, we developed a fatigue severity scale, subjected it to tests of internal consistency and validity, and used it to compare fatigue in two chronic conditions: systemic lupus erythematosus and multiple sclerosis. Administration of the fatigue severity scale to 25 patients with multiple sclerosis, 29 patients with systemic lupus erythematosus, and 20 healthy adults revealed that the fatigue severity scale was internally consistent, correlated well with visual analogue measures, clearly differentiated controls from patients, and could detect clinically predicted changes in fatigue over time. Fatigue had a greater deleterious impact on daily living in patients with multiple sclerosis and systemic lupus erythematosus compared with controls. The results further showed that fatigue was largely independent of self-reported depressive symptoms and that several characteristics could differentiate fatigue that accompanies multiple sclerosis from fatigue that accompanies systemic lupus erythematosus. This study demonstrates (1) the clinical and research applications of a scale that measures fatigue severity and (2) helps to identify features that distinguish fatigue between two chronic medical disorders.