CONTEXT: Disease-modifying multiple sclerosis (MS) therapeutic trials continue to rely on physical disability as the main clinical outcome measure, while the impact of treatment on quality of life (QOL) is poorly understood. Weak correlations exist between physical disability and the disease burden as shown using conventional brain magnetic resonance imaging (MRI), indicating poor sensitivities of these measures alone in defining the clinical course of MS. OBJECTIVES: To investigate the impact of MS on QOL; to determine whether impaired QOL in patients with MS was related to any regional brain abnormalities assessed using conventional MRI sequences; and to determine if the severity of MS as assessed by the Expanded Disability Status Scale (EDSS) and clinical course was associated with worsening QOL. DESIGN, SETTING, AND PATIENTS: Prospective, cross-sectional study of 60 consecutive patients with MS treated in a community-based, university-affiliated MS clinic. MAIN OUTCOME MEASURES: Assessments of QOL using the Multiple Sclerosis Quality of Life-54 Instrument were correlated with the scores of the EDSS, clinical course, and findings on brain MRI. RESULTS: Quality of life was significantly impaired in patients with MS and was worse in patients with secondary-progressive MS compared with those with relapsing-remitting MS. Brain MRI lesions and atrophy were associated with impaired QOL with respect to sexual dysfunction, overall mental health, and limitations due to physical and emotional dysfunction. Correlations between MRI results and QOL assessments were much stronger for hypointense lesions and atrophy on T1-weighted images than for hyperintense lesions on T2-weighted images and were insignificant for lesions on contrast-enhanced images. Higher EDSS scores were associated with impairments in most physical and mental health QOL scales but were weakly correlated with cognitive and sexual dysfunction. CONCLUSIONS: In patients with MS, QOL is impaired and is associated with increasing neurologic disability. Quality of life assessments are related in part to brain lesions and atrophy shown on MRI. Assessments of QOL provide unique information not readily evaluated by EDSS and may be useful as secondary clinical outcome measures. Arch Neurol. 2000;57:1485-1491