Multiple sclerosis (MS) can influence all aspects of a patient's health. This study determines the main factors affecting quality of life (QoL) in Iranian MS patients. QoL (Multiple Sclerosis Impact Scale; MSIS-29), disability (Expanded Disability Status Scale; EDSS) and depression (Beck Depression Inventory; BDI) were assessed in 106 MS patients. EDSS, clinical course and MS duration significantly correlated with physical MSIS-29. Depression highly correlated with both physical and psychological MSIS-29. Regression analyses showed that depression and EDSS predicted physical health. Psychological health was predicted by depression. These findings highlight that depression and physical disability strongly influence QoL in Iranian MS patients.