Current knowledge about the health-related quality of life (HRQoL) experienced by people with multiple sclerosis (MS) is limited. We compared item and component scale scores on the Medical Outcomes Short Form 12 (SF-12) of 2,109 people with MS to U.S. norms and published data on persons with other medical conditions. We also built regression models for SF-12-derived mental (MCS) and physical component scale (PCS) scores. Seventy-five percent of the sample had been diagnosed with MS for over 5 years, and one-half to two-thirds received help with at least one activity of daily living (ADL) or instrumental activity of daily living (IADL), respectively. The mean PCS score was 36.2 (Standard Error: 0.27), significantly lower by 14 points than the U.S. population norm and by 4–12 points than mean scores for individuals with diabetes, congestive heart failure, myocardial infarction, hypertension or depression. The mean MCS score was 49.2 (Standard Error: 0.25), significantly lower than the norm for the U.S. population and the mean scores for the chronic condition groups except congestive heart failure and depression. We identified several demographic, disease, and health services factors that were significantly related to quality of life and highlighted a number of areas for improvement. We concluded that the quality of the lives of people with MS could be enhanced by removing barriers to MS care, general health care, and mental health care; meeting needs for help with activities of daily living and instrumental activities of daily living; supporting employment; and improving access to disease modifying agents and symptomatic treatments.