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Background & Objectives: For those with a chronic illness, suffering may result not only from physical limitations, but also from the psychosocial consequences of having a chronic condition. Therefore, simply measuring physical health is not enough anymore. It is necessary to evaluate quality of life as an important clinical outcome in these patients. We conducted the present study to measure quality of life (QoL) in multiple sclerosis (MS) patients and its predictors in comparison with the general population in Tehran, using a generic and overall QoL instrument, the WHOQOL-BREF (World Health Organization Quality of Life-BREIF). This questionnaire comprises four domains including physical health, mental health, social relationships, and environmental health. For each domain, scores range from 4 to 20, higher scores corresponding to a more favorable QOL. Methods: This study was of cross-sectional type and involved 145 selected systematically patients registered in the Iranian Multiple Sclerosis Society. The WHOQOL-Questionnaire was filled in for these patients through telephone interviews. The results were compared with quality of life scores from the general population obtained from a population-based study in Tehran. Multiple regression was used for data analysis. Results: The response rate was 97%; 73.8% of participants were female, the mean age of participants was 36.5 (SD = 10.4) years, and the mean years of their formal education was 12.5 (SD=3.6). Mean scores for physical health, psychological health, social relationship and environmental health were 11.5 (SD=3.2), 11.8 (SD=3.2), 12.7 (SD=3.1), and 11.5 (SD=2.7), respectively. In comparison with the general population, the patients' scores in all domains were significantly lower than in the general population. Severity of disease and education level had a relationship with domain scores in regression analysis. Conclusions: The WHOQOL-BREF questionnaire can discriminate between these patients’ quality of life and that of the general population and show the effect of disease severity and demographic variables on quality of life. Therefore the questionnaire can be used in this group of patients, although it may be necessary to add some specific questions to make the tool more sensitive in evaluating quality of life from a clinical perspective. Educational interventions are recommended to improve quality of life in this group of patients.