Multiple sclerosis is responsible for impairment and disability, which play a major role in the personal burden of the disease. Health-related quality of life (HRQoL) has been intensively studied in this medical condition, more intensively than in other chronic neurological disorders, perhaps because of the limitations of the conventional disability instruments, which seem less sensitive to change. Moreover, HRQoL measurements can summarize all sources of patient satisfaction and dissatisfaction. Instead of relying on motor limitations, many psychological, social, and neuropsychological factors, such as cognitive impairment and fatigue, are predictors of a reduced quality of life, even in the early stages, more than conventional radiological MRI. The analysis of self-administered HRQoL questionnaires, generic or mixed (specific and generic), can help clinicians advance toward the best therapeutic approach for the patient.