Objective: It was aimed in this study to determine the frequency and severity of fatigue and to investigate its relation to depression, disability level, and cognitive status in patients with multiple sclerosis.Patients and Methods: Seventy-nine multiple sclerosis patients, attending the outpatient multiple sclerosis clinic in our hospital, were recruited. The fatigue severity, disability level, cognitive status and depression were evaluated by using “Fatigue Severity Scale (FSS), Expanded Disability Status Scale (EDSS), Mini Mental Status Examination (MMSE) and Beck Depression Inventory (BDI) respectively. The relation between fatigue and the other parameters was measured by Spearman rank correlation analysis. To determine the most powerfull determinant of fatigue, multipl regression analysis was used.Results: The mean age of patients was 40.6±10.3 year, and the mean disease duration was 5 (1-32) [median (range)] year. It was determined that fatigue was present in 50.7% (N=40) of patients. When comparing fatigued (N=40) and nonfatigued (N=29) patients, EDSS and BDI scores were higher and duration of education and MMSE scores were lower in patients with fatigue (p<0.05). The severity of fatigue was significantly correlated to cognitive status and depression score (r= -0.301, p= 0.034; r= 0.419, p= 0.002 respectively). Regression analysis revealed that, the most powerfull determinant of fatigue is depression (r2= 0.179, p=0.002).Conclusion: In patients with multiple sclerosis, fatigue shouldn't be perceived as an physical outcome related only to disability level. Our data show that, fatigue should be interpreted as a symptom associated with depression in the course of rehabilitation of patients with multiple sclerosis.