Background: Fatigue is experienced by most patients with multiple sclerosis (MS) and often is profoundly debilitating. No large-scale studies to our knowledge have examined circadian rhythm abnormalities in MS patients or the relationship of fatigue to circadian rhythms. Objective: To determine if patients with MS and fatigue have sleep disturbances or circadian rhythm abnormalities associated with fatigue. Design: Case-control study. Setting: Washington University School of Medicine, St Louis, Mo. Patients: Fifteen patients with MS and fatigue were compared with 15 patients with MS without fatigue and 15 age- and sex-matched, healthy controls. Main Outcome Measures: Sleep disturbances and circadian rhythm abnormalities were quantitated by actigraphy, fatigue by the Fatigue Descriptive Scale, and excessive sleepiness by the Epworth Sleepiness scale (ESS). Results: Of the 15 fatigued patients with MS, 2 had delayed sleep phase, 10 had disrupted sleep, and 3 had normal sleep. One of the 15 nonfatigued MS patients had irregular sleep cycles, 2 others had disrupted sleep, and 12 had normal sleep. All 15 of the healthy controls had normal sleep. Nine patients with MS and fatigue scored 10 or higher on the ESS, suggesting excessive daytime sleepiness. Only 2 patients with MS without fatigue scored higher than 10 on the ESS. None of the healthy controls were fatigued, and 14 were not excessively sleepy. A relationship was found between fatigue and abnormal sleep cycles or disrupted sleep (Fisher exact test, P=.003). There was also a relationship between subjective excessive daytime sleepiness and fatigue in MS patients (P=.02). Conclusion: There is a significant correlation between fatigue in MS patients and disrupted sleep or abnormal sleep cycles.