Health-related quality of life (HQOL) is poor in multiple sclerosis(MS) but t he clinical precipitants of the problem are not well understood. Previous correl ative studies demonstrated relationships between various clinical parameters and diminished HQOL in MS. Unfortunately, these studies failed to account for multi ple predictors in the same analysis. We endeavored to determine what clinical pa rameters account for most variance in predicting HQOL, and employ ability, while accounting for disease course, physical disability, fatigue, cognition, mood di sorder,personality, and behavior disorder. In 120 MS patients,we measured HQOL ( MS Quality of Life-54) and vocational status (employed vs. disabled) and then c onducted detailed clinical testing. Data were analyzed by linear and logistic re gression methods. MS patients reported lower HQOL (p < 0.001) and were more like ly to be disabled (45%of patients vs. 0 controls).Physical HQOL was predicted b y fatigue, depression,and physical disability. Mental HQOL was associated with o nly depression and fatigue. In contrast, vocational status was predicted by thre e cognitive tests, conscientiousness, and disease duration (p < 0.05). Thus, for the first time, we predicted HQOL in MS while accounting for measures from thes e many clinical domains. We conclude that self-report HQOL indices are most str ongly predicted by measures of depression,whereas vocational status is predicted primarily by objective measures of cognitive function. The findings highlight c ore clinical problems that merit early identification and further research regar ding the development of effective treatment. Health-related quality of life (HQOL) is poor in multiple sclerosis (MS) but t he clinical precipitants of the problem are not well understood. Previous correl ative studies of relationships between various clinical parameters and diminished HQOL in MS. Unfortunately, these studies failed to account for multi ple predictors in the same analysis. We endeavored to determine what clinical pa rameters account for most variance in predicting HQOL, and employ ability, while accounting for disease course, physical disability, fatigue, cognition, mood di sorder, personality , and behavior disorder. In 120 MS patients, we measured HQOL (MS Quality of Life-54) and vocational status (employed vs. disabled) and then c onducted detailed clinical testing. Data were analyzed by linear and logistic re gression methods. MS Patients reported lower HQOL (p <0.001) and were more like ly to be disabled (45% of patients vs. 0 controls). Physiological HQOL was predicted by fatigue, depression, and physical In contrast, vocational status was predicted by threet cognitive tests, conscientiousness, and disease duration (p <0.05). In contrast, vocational status was predicted by threet cognitive tests, conscientiousness, and disease duration accounting for measures from thes e many clinical domains. We conclude that self-report HQOL indices are most str ongly predicted by measures of depression, that vocational status is bored to objective measures of cognitive function. The findings highlight c ore clinical problems that merit early identification and further research regar ding the development of effective treatment.