Previous studies of personality change in multiple sclerosis (MS) relied on brief, nonstandardized assessments or tests that are confounded with symptoms of acute psychiatric disorder. Objectives of the present study were to evaluate character change in MS by using comprehensive trait measures of personality and to determine if there is an association between personality change and cognitive dysfunction. Thirty-four MS patients and 14 healthy volunteers were studied. All underwent comprehensive neurologic and neuropsychologic evaluation. Personality assessments included both self and informant reports on the Hogan Empathy Scale and the NEO Personality Inventory. Abnormalities were found among MS patients indicating elevated neuroticism and reduction in empathy, agreeableness, and conscientiousness. Large patient/informant discrepancies were observed in the MS but not the control group. Three neuropsychological tests emphasizing executive control predicted the presence of these abnormalities; this association suggests a neurogenic, frontal lobe syndrome.