Background: Circadian rhythm sleep disorders are a presentation of sleep disorders in patients with multiple sclerosis (MS). This study aims to compare this problem in MS patients with healthy people and to determine its association with chronic fatigue in MS patients. Materials and Methods: A case-control study was performed on 120 MS patients and 60 healthy subjects matched for age and sex, in 2009 in MS Clinic Alzahra Hospital. Sleep quality, rhythm and fatigue severity were assessed using PSQI (Pittsburgh sleep quality index) and FSS (Fatigue severity Scale) questionnaires, respectively. Its reliability and validity has been confirmed in several studies (Cronbach′s alpha = 0.83). This index has seven sections including patient′s assessment of his/her sleep, sleep duration, efficacy of routine sleep, sleep disorders, use of hypnotic medication, and dysfunction in daily activities. Results: Circadian rhythm sleep disorder was more frequent in MS patients relative to healthy subjects (P: 0.002). It was higher in MS patients with severe fatigue relative to MS patients with mild fatigue (P: 0.05). Fatigue severity was 49.9 ± 8.2 and 22.5 ± 7.4 in the first and second group, respectively. PSQI index was 7.9 ± 4.5 in patients with severe fatigue and 5.9 ± 4.5 in patients with mild fatigue and 4.5 ± 2.4 in the control group (P: 0.0001). Conclusion: Circadian rhythm sleep disorders are more frequent in MS patients and those with fatigue. Recognition and management of circadian rhythm sleep disorders in MS patients, especially those with fatigue may be helpful in improving care of these patients.