Background & Aims: Fatigue Severity Scale (FSS), due to its simple and clinical nature, is frequently used to measure fatigue level in patients. Since fatigue is a common symptom in multiple sclerosis (MS) disorder, the present study aimed at evaluating the psychometric properties of the Persian version of FSS in patients with MS. Methods: This study was descriptive and of a validation type, in which 162 patients were selected by consecutive sampling. Internal consistency reliability and construction, concurrent and predictive validity of this scale were examined. Subjects completed the Depression Anxiety Stress Scale (DASS-21) and Physical Dimensions of 36-item Health Survey Questionnaire (SF-36). Results: Internal consistency of FSS was excellent (Cronbach's Alpha =0.93). Coefficient of item-total correlation for each item was in acceptable range of 0.43 to 0.85. Results of the concurrent validity showed that FSS has a good correlation with all structures associated with research tools, based on the expected directions (P< 0.0001). Also scores of fatigue scale predicted a significant proportion of the variance in scores on measures of depression, anxiety, and physical dimensions of quality of life, even after controlling confounding effects of age, sex, marital status and educational level. Conclusion: Findings suggest that Persian version of FSS has satisfactory psychometric properties and is applicable in research and clinical activities relating to MS patients.