Quality of Life (QOL) is impaired in multiple sclerosis (MS) in part due to physical disability. MS-associated fatigue (MSF) and depression (MSD) are common and treatable features of MS, which could also impact on QOL, independent of physical disability. We prospectively studied 60 consecutive patients with MS. QOL was assessed using Multiple Sclerosis Quality of Life (MSQOL)-54. Group differences in QOL scores were assessed after adjusting for Expanded Disability Status Scale (EDSS), Fatigue Severity Scale (FSS) and Hamilton Depression Inventory scores. MS patients were grouped into relapsing-remitting (RR) or secondary-progressive (SP), MSF (FSS> or =5) or MS-nonfatigue (MSNF) (FSS< or =4), and MSD or MS-nondepression (MSND). After accounting for disability and depression, fatigue was associated with impaired QOL with respect to health perception (p=0.03) and limitations due to physical dysfunction (p=0.008). After accounting for disability and fatigue, depression was associated with lower QOL with respect to health perception (p=0.02), sexual dysfunction (p=0.03), health distress (p=0.03), mental health (p=0.006), overall QOL (p=0.006), emotional dysfunction (p=0.04), and limitations due to emotional dysfunction (p=0.03). This study demonstrates that fatigue and depression are independently associated with impaired QOL in MS, after accounting for physical disability, suggesting that their recognition and treatment can potentially improve QOL.